Anti-tumor effect of the alphavirus-based virus-like particle vector expressing prostate-specific antigen in a HLA–DR transgenic mouse model of prostate cancer

The goal of this study was to determine if an alphavirus-based vaccine encoding human Prostate-Specific Antigen (PSA) could generate an effective anti-tumor immune response in a stringent mouse model of prostate cancer. DR2bxPSA F₁ male mice expressing human PSA and HLA-DRB1^*1501 transgenes were vaccinated with virus-like particle vector encoding PSA (VLPV–PSA) followed by the challenge with Transgenic Adenocarcinoma of Mouse Prostate cells engineered to express PSA (TRAMP–PSA). PSA-specific cellular and humoral immune responses were measured before and after tumor challenge. PSA and CD8 reactivity in the tumors was detected by immunohistochemistry. Tumor growth was compared in vaccinated and control groups. We found that VLPV–PSA could infect mouse dendritic cells in vitro and induce a robust PSA-specific immune response in vivo. A substantial proportion of splenic CD8 T cells (19.6 ± 7.4%) produced IFNγ in response to the immunodominant peptide PSA_65–73. In the blood of vaccinated mice, 18.4 ± 4.1% of CD8 T cells were PSA-specific as determined by the staining with H-2D^b/PSA_65–73 dextramers. VLPV–PSA vaccination also strongly stimulated production of IgG2a/b anti-PSA antibodies. Tumors in vaccinated mice showed low levels of PSA expression and significant CD8+ T cell infiltration. Tumor growth in VLPV–PSA vaccinated mice was significantly delayed at early time points (p = 0.002, Gehan–Breslow test). Our data suggest that TC-83-based VLPV–PSA vaccine can efficiently overcome immune tolerance to PSA, mediate rapid clearance of PSA-expressing tumor cells and delay tumor growth. The VLPV–PSA vaccine will undergo further testing for the immunotherapy of prostate cancer.     

A single dose and long lasting vaccine against pandemic influenza through the controlled release of a heterospecies tandem M2 sequence embedded within detoxified bacterial outer membrane vesicles

The influenza A virus undergoes genetic drift and shift, leaving the general population susceptible to emerging pandemic strains, despite seasonal flu vaccination. Here we describe a single dose influenza vaccine derived from recombinant outer membrane vesicles (rOMVs) that display an antigen-mapped heterospecies tandem sequence of the M2 protein from the influenza A virus, released over 30 days from poly(lactic-co-glycolide) (PLGA) microparticles. Four weeks post vaccination, BALB/c mice developed high anti-M2e IgG titers that were equivalent to those generated at 8 weeks in a typical prime/boost vaccine regimen. Challenge of mice with a lethal dose of mouse adapted influenza virus PR8 (H1N1) 10 weeks post vaccination resulted in 100% survival for both rOMV single-dose microparticle and prime/boost vaccinated mice. Anti-M2e IgG1 and IgG2a antibody titers were weighted toward IgG1, but splenocytes isolated from rOMV single-dose microparticle vaccinated mice produced high levels of IFNγ relative to IL-4 in response to stimulation with M2e peptides, supporting a more Th1 biased immune response. The protective immune response was long lasting, eliciting sustained antibody titers and 100% survival of mice challenged with a lethal dose of PR8 six months post initial vaccination. Together, these data support the potential of controlled release rOMVs as an effective single dose, long lasting and rapidly effective vaccine to protect against influenza.     

Vaccination with a live attenuated Acinetobacter baumannii deficient in thioredoxin provides protection against systemic Acinetobacter infection

Multi-drug resistant Acinetobacter baumannii (MDR-Ab), an opportunistic pathogen associated with nosocomial and combat related infections, has a high mortality due to its virulence and limited treatment options. Deletion of the thioredoxin gene (TrxA) from a clinical isolate of MDR-Ab resulted in a 100-fold increase in 50% lethal dose (LD₅₀) in a systemic challenge murine model. Thus, we investigated the potential use of this attenuated strain as a live vaccine against MDR-Ab. Mice were vaccinated by subcutaneous (s.c.) injection of 2 × 10⁵ CFU of the ΔtrxA mutant, boosted 14 days later with an equivalent inoculum, and then challenged 30 days post-vaccination by i.p. injection with 10 LD₅₀ of the wild type (WT) Ci79 strain. Efficacy of vaccination was evaluated by monitoring MDR-Ab specific antibody titers and cytokine production, observing pathology and organ burdens after WT challenge, and measuring levels of serum pentraxin-3, a molecular correlate of A. baumannii infection severity, before and after challenge. Mice vaccinated with ΔtrxA were fully protected against the lethal challenge of WT. However, minimal immunoglobulin class switching was observed with IgM predominating. Spleens harvested from vaccinated mice exhibited negligible levels of IL-4, IFN-γ and IL-17 production when stimulated with UV-inactivated WT Ci79. Importantly, tissues obtained from vaccinated mice displayed reduced pathology and organ burden compared to challenged non-vaccinated mice. Additionally, serum pentraxin-3 concentrations were not increased 24 h after challenge in vaccinated mice, correlating with reduction of WT MDR-Ab infection in ΔtrxA immunized mice. Furthermore, passive immunization with ΔtrxA-immune sera provided protection against lethal systemic Ci79 challenge. Collectively, the defined live attenuated ΔtrxA strain is a vaccine candidate against emerging MDR Acinetobacter infection.     

Expression of fibronectin binding protein A (FnBPA) from Staphylococcus aureus at the cell surface of Lactococcus lactis improves its immunomodulatory properties when used as protein delivery vector

A recombinant strain of Lactococcus lactis displaying a cell-surface anchored fibronectin binding protein A (FnBPA) from Staphylococcus aureus (LL-FnBPA) had been shown to be more efficient in delivering plasmid than its wild-type counterpart both in vitro and in vivo, and have the ability to orientate the immune response toward a Th2 profile in a context of a DNA vaccination. The aim of this work was to test whether this LL-FnBPA strain could shape the immune response after mucosal administration in mice. For this, we used a mouse model of human papilloma virus (HPV)-induced cancer and a L. lactis strain displaying at its cell surface both HPV-16-E7 antigen (LL-E7) and FnBPA (LL-E7 + FnBPA). Our results revealed a more efficient systemic Th1 immune response with recombinant LL-E7 + FnBPA. Furthermore, mice vaccinated with LL-E7 + FnBPA were better protected when challenged with HPV-16-induced tumors. Altogether, the results suggest that FnBPA displays adjuvant properties when used in the context of mucosal delivery using L. lactis as a live vector.     

Development of a subunit vaccine containing recombinant Riemerella anatipestifer outer membrane protein A and CpG ODN adjuvant

Riemerella anatipestifer, a Gram-negative bacillus, causes septicemia that can result in high mortality for ducklings. In this study, we evaluated the immune response and protective efficacy provided by a subunit vaccine containing recombinant outer membrane protein A (rOmpA) and plasmid constructs containing CpG oligodeoxynucleotides (ODN). Results showed that CpG ODN enhanced both humoral and cell-mediated immunity elicited by rOmpA as early as two weeks after primary immunization. When compared to ducks immunized with rOmpA, ducks immunized with rOmpA + CpG ODN showed higher levels (p < 0.05) of antibody titer, T cell proliferation, and percentages of CD4⁺ and CD8⁺ T cell in peripheral blood mononuclear cells (PBMCs). The relative fold inductions of mRNA expression of Th1-type (IFN-γ and IL-12), and Th2-type (IL-6) cytokines in PBMCs isolated from ducks immunized with rOmpA + CpG ODN were significantly higher than those of the rOmpA group. Homologous challenge result showed that the rOmpA + CpG ODN vaccine reduced the pathological score by 90% in comparison with the saline control. In conclusion, our study found that CpG ODN can enhance both humoral and cellular immunity elicited by a rOmpA vaccine. The rOmpA + CpG ODN vaccine can be further developed as a subunit vaccine against R. anatipestifer.     

KISS1 can be used as a novel target for developing a DNA immunocastration vaccine in ram lambs

KISS1 gene-encoding kisspeptins are critical for the onset of puberty and control of adult fertility. This study investigated whether KISS1 can be used as a novel target for immunocastration. Human KISS1 was fused with the HBsAg-S gene for constructing an antibiotic-free recombinant plasmid pKS-asd that coded for 31.168 kDa target fusion protein. Six male Hu sheep lambs were divided into two equal groups, treatment and control. The vaccine (1 mg/ram lamb) prepared in saline solution was injected into lambs at weeks 0, 3 and 6 of the experiment, respectively. Vaccine efficacy was evaluated in terms of KISS1-specific IgG antibody response, serum testosterone levels, scrotal circumference, testicular weight, length and breadth, extent of testicular tissue damage, and sexual behaviour changes. The specific anti-KISS1 antibody titre in vaccinated animals was significantly higher than that in controls (p < 0.05). In addition, vaccinated animals showed lower serum testosterone level, testicular weight and length and smaller scrotal circumference than those in controls (p < 0.05). Spermatogenesis of seminiferous tubules in vaccinated animals was suppressed; sexual behaviours in vaccinated animals were significantly lower (p < 0.05) than those in controls. In conclusion, the immunization against KISS1 in this DNA vaccine induced a strong antibody response and resulted in the suppression of gonadal function and sexual behaviour in animals, demonstrating that KISS1 can be used as a novel target for developing a DNA immunocastration vaccine.     

Protection of non-human primates against glanders with a gold nanoparticle glycoconjugate vaccine

The Gram-negative Burkholderia mallei is a zoonotic pathogen and the causative agent of glanders disease. Because the bacteria maintain the potential to be used as a biothreat agent, vaccine strategies are required for human glanders prophylaxis. A rhesus macaque (Macaca mulatta) model of pneumonic (inhalational) glanders was established and the protective properties of a nanoparticle glycoconjugate vaccine composed of Burkholderia thailandensis LPS conjugated to FliC was evaluated. An aerosol challenge dose of ∼1 × 10⁴ CFU B. mallei produced mortality in 50% of naïve animals (n = 2/4), 2–3 days post-exposure. Although survival benefit was not observed by vaccination with a glycoconjugate glanders vaccine (p = 0.42), serum LPS-specific IgG titers were significantly higher on day 80 in 3 vaccinated animals who survived compared with 3 vaccinated animals who died. Furthermore, B. mallei was isolated from multiple organs of both non-vaccinated survivors, but not from any organs of 3 vaccinated survivors at 30 days post-challenge. Taken together, this is the first time a candidate vaccine has been evaluated in a non-human primate aerosol model of glanders and represents the initial step for consideration in pre-clinical studies.     

A novel liposome adjuvant DPC mediates Mycobacterium tuberculosis subunit vaccine well to induce cell-mediated immunity and high protective efficacy in mice

Tuberculosis (TB) is a serious disease around the world, and protein based subunit vaccine is supposed to be a kind of promising novel vaccine against it. However, there is no effective adjuvant available in clinic to activate cell-mediated immune responses which is required for TB subunit vaccine. Therefore, it is imperative to develop new adjuvant. Here we reported an adjuvant composed of dimethyl dioctadecylammonium (DDA), Poly I:C and cholesterol (DPC for short). DDA can form a kind of cationic liposome with the ability to deliver and present antigen and can induce Th1 type cell-mediated immune response. Poly I:C, a ligand of TLR3 receptor, could attenuate the pathologic reaction induced by following Mycobacterium tuberculosis challenge. Cholesterol, which could enhance rigidity of lipid bilayer, is added to DDA and Poly I:C to improve the stability of the adjuvant. The particle size and Zeta-potential of DPC were analyzed in vitro. Furthermore, DPC was mixed with a TB fusion protein ESAT6-Ag85B-MPT64(190-198)-Mtb8.4-Rv2626c (LT70) to construct a subunit vaccine. The subunit vaccine-induced immune responses and protective efficacy against M. tuberculosis H37Rv infection in C57BL/6 mice were investigated. The results showed that the DPC adjuvant with particle size of 400 nm and zeta potential of 40 mV was in good stability. LT70 in the adjuvant of DPC generated strong antigen-specific humoral and cell-mediated immunity, and induced long-term higher protective efficacy against M. tuberculosis infection (5.41 ± 0.38 log₁₀ CFU) than traditional vaccine Bacillus Calmette–Guerin (BCG) (6.01 ± 0.33 log₁₀ CFU) and PBS control (6.53 ± 0.26 log₁₀ CFU) at 30 weeks post-vaccination. In conclusion, DPC would be a promising vaccine adjuvant with the ability to stimulate Th1 type cell-mediated immunity, and could be used in TB subunit vaccine.     

Vaccine-associated reduction in symptom severity among patients with influenza A/H3N2 disease

BackgroundThe moderate level of protection conferred by influenza vaccines is well-known, but the vaccine's ability to attenuate symptom severity among vaccinated individuals (i.e., vaccine failures) has not been established.MethodsWe enrolled otherwise healthy adults who presented with influenza-like illness (ILI) at five US military hospitals between 2009 and 2014. Influenza was diagnosed and subtyped by PCR. Individual and composite severity scores were compared between those who had vs. had not received the seasonal influenza vaccine >14 days prior to enrollment.ResultsA total of 155 cases of influenza (A/H1N1, n = 69; A/H3N2, n = 66; A/untyped, n = 3; B, n = 17) were identified, of whom 111 (72%; A/H1N1, n = 44; A/H3N2, n = 52; A/untyped, n = 3; B, n = 12) had been vaccinated. Women were significantly less likely to be vaccinated than men (49% vs. 89%; p < 0.01). In multivariate analysis, vaccinated individuals were significantly less likely to report a fever >101 °F (OR 0.24; 95% CI [0.10, 0.62]) and more likely to report myalgias (OR 3.31; 95% CI [1.22, 8.97]) than vaccinated individuals. Among patients with A/H3N2 infection, upper respiratory and total symptom severity scores were significantly lower for vaccinated patients during the first 2 days of illness, and differences in total symptom severity persisted over 7 days (p < 0.05 for all comparisons). Differences across additional symptom categories (lower respiratory and systemic) were also observed throughout 7 days of illness in bivariate analyses. Differences in symptom severity were not observed between vaccinated and unvaccinated participants with A/H1N1 infection.ConclusionsAmong patients with A/H3N2 infection, receipt of seasonal influenza vaccine was associated with reduced symptom severity. Patient-centered discussion about the benefits of influenza vaccination should be expanded to include the possibility that the vaccine could attenuate symptoms.     

Staphylococcus aureus avirulent mutant vaccine induces humoral and cellular immune responses on pregnant heifers

Bovine mastitis produces economic losses, attributable to the decrease in milk production, reduced milk quality, costs of treatment and replacement of animals. A successful prophylactic vaccine against Staphylococcus aureus should elicit both humoral and cellular immune responses. In a previous report we evaluated the effectiveness of a live vaccine to protect heifers against challenge with a virulent strain. In the present study the immunological response of heifers after combined immunization schedule was investigated. In a first experimental trial, heifers were vaccinated with 3 subcutaneous doses of avirulent mutant S. aureus RC122 before calving and one intramammary dose (IMD) after calving. Antibodies concentration in blood, bactericidal effect of serum from vaccinated animals and lymphocyte proliferation was determined. The levels of total IgG, IgG1 and IgG2 in colostrum and the lymphocyte proliferation index were significantly higher in vaccinated respect to non-vaccinated group throughout the experiment. The second trial, where animals were inoculated with different vaccination schedules, was carried out to determine the effect of the IMD on the level of antibodies in blood and milk, cytokines (IL-13 and IFN-γ) concentration and milk's SCC and bacteriology. The bacterial growth of the S. aureus strains was totally inhibited at 1–3 × 10⁶ and 1–3 × 10³ cfu/ml, when the strains were mixed with pooled serum diluted 1/40. The results shown that IMD has not a significant effect on the features determinate. In conclusion, a vaccination schedule involving three SC doses before calving would be enough to stimulate antibodies production in milk without an IMD. Furthermore, the results showed a bactericidal effect of serum from vaccinated animals and this provides further evidence about serum functionality. Immune responses, humoral (antigen-specific antibodies and Th2 type cytokines) and cellular (T-lymphocyte proliferation responses and Th1 type cytokines), were augmented by administration of the avirulent mutant which represent an antigenic pool.     

Multiple efficacy studies of an adenovirus-vectored foot-and-mouth disease virus serotype A24 subunit vaccine in cattle using homologous challenge

The safety and efficacy of an experimental, replication-deficient, human adenovirus-vectored foot-and-mouth disease virus (FMDV) serotype A24 Cruzeiro capsid-based subunit vaccine (AdtA24) was examined in eight independent cattle studies. AdtA24 non-adjuvanted vaccine was administered intramuscularly to a total of 150 steers in doses ranging from approximately 1.0 × 10⁸ to 2.1 × 10¹¹ particle units per animal. No detectable local or systemic reactions were observed after vaccination. At 7 days post-vaccination (dpv), vaccinated and control animals were challenged with FMDV serotype A24 Cruzeiro via the intradermal lingual route. Vaccine efficacy was measured by FMDV A24 serum neutralizing titers and by protection from clinical disease and viremia after challenge. The results of eight studies demonstrated a strong correlation between AdtA24 vaccine dose and protection from clinical disease (R² = 0.97) and viremia (R² = 0.98). There was also a strong correlation between FMDV A24 neutralization titers on day of challenge and protection from clinical disease (R² = 0.99). Vaccination with AdtA24 enabled differentiation of infected from vaccinated animals (DIVA) as demonstrated by the absence of antibodies to the FMDV nonstructural proteins in vaccinates prior to challenge. Lack of AdtA24 vaccine shedding after vaccination was indicated by the absence of neutralizing antibody titers to both the adenovector and FMDV A24 Cruzeiro in control animals after co-mingling with vaccinated cattle for three to four weeks. In summary, a non-adjuvanted AdtA24 experimental vaccine was shown to be safe, immunogenic, consistently protected cattle at 7 dpv against direct, homologous FMDV challenge, and enabled differentiation of infected from vaccinated cattle prior to challenge.     

MultiTEP platform-based DNA epitope vaccine targeting N-terminus of tau induces strong immune responses and reduces tau pathology in THY-Tau22 mice

Background: By the time clinical symptoms of Alzheimer’s disease (AD) manifest in patients there is already substantial tau pathology in the brain. Recent evidence also suggests that tau pathology can become self-propagating, further accelerating disease progression. Over the last decade several groups have tested the efficacy of protein-based anti-tau immunotherapeutics in various animal models of tauopathy. Here we report on the immunological and therapeutic potency of the first anti-tau DNA vaccine based on the MultiTEP platform, AV-1980D, in THY-Tau22 transgenic mice. Methods: Starting at 3 months of age, mice were immunized intramuscularly with AV-1980D vaccine targeting a tau B cell epitope spanning aa2-18 followed by electroporation (EP). Humoral and cellular immune responses in vaccinated animals were analyzed by ELISA and ELISpot, respectively. Neuropathological changes in the brains of experimental and control mice were then analyzed by biochemical (WB and ELISA) and immunohistochemical (IHC) methods at 9 months of age. Results: EP-mediated AV-1980D vaccinations of THY-Tau22 mice induced activation of Th cells specific to the MultiTEP vaccine platform and triggered robust humoral immunity response specific to tau. Importantly, no activation of potentially harmful autoreactive Th cell responses specific to endogenous tau species was detected. The maximum titers of anti-tau antibodies were reached after two immunizations and remained slightly lower, but steady during five subsequent monthly immunizations. Vaccinations with AV-1980D followed by EP significantly reduced total tau and pS199 and AT180 phosphorylated tau levels in the brains extracts of vaccinated mice, but produced on subtle non-significant effects on other phosphorylated tau species. Conclusions: These data demonstrate that MultiTEP-based DNA epitope vaccination targeting the N-terminus of tau is highly immunogenic and therapeutically potent in the THY-Tau22 mouse model of tauopathy and indicate that EP-mediated DNA immunization is an attractive alternative to protein-based adjuvanted vaccines for inducing high concentrations of anti-tau antibodies.     

Trivalent pneumococcal protein vaccine protects against experimental acute otitis media caused by Streptococcus pneumoniae in an infant murine model

BackgroundCurrently licensed serotype-based pneumococcal vaccines are effective in preventing invasive pneumococcal diseases, but less effective in preventing non-bacteremic pneumonia and acute otitis media (AOM). We previously reported that a trivalent pneumococcal protein recombinant vaccine (PPrV) protected against pneumonia in a murine model. Here we evaluated PPrV protection against AOM in an infant murine model.MethodsC57BL/6J mice were intramuscularly vaccinated at 1–3 weeks of age with monovalent pneumococcal histidine triad protein D (PhtD), or pneumococcal choline binding protein A (PcpA), or detoxified pneumolysin (PlyD1), or trivalent vaccine, and transtympanically challenged at 7–8 weeks of age with 1 × 10² CFU of pneumococcal strain BG7322 (6A) or 1 × 10⁴ CFU of pneumococcal nontypeable strain 0702064 MEF. Serum IgG titers were determined by ELISA. At 24 and 48 h post infection (hpi), animals were sacrificed and middle ear fluid (MEF) samples were collected to determine pneumococcal CFUs.ResultsWe found that vaccination of infant mice with monovalent and trivalent pneumococcal proteins elicited significant serum IgG antibody responses to corresponding component proteins. Vaccination with PhtD reduced BG7322 bacterial burdens in MEF at both 24 (p = 0.05) and 48 hpi (p = 0.16). Vaccination with PcpA significantly reduced the bacterial burdens in MEF at both 24 (p = 0.02) and 48 hpi (p = 0.004), and PlyD1 significantly reduced bacterial burden in MEF at 48 hpi (p = 0.02). Vaccination with trivalent PPrV (PhtD, PcpA and PlyD1) significantly reduced Spn burdens in MEF at both 24 (p = 0.001) and 48 hpi (p < 0.0001). Similar reductions of bacterial burdens were found when the vaccinated animals were challenged with a non-typeable Spn strain. Vaccinated mice had significantly milder inflammatory cytokine levels (IL-1β, IL-6, TNF-α, MIP-2 and KC) in middle ears at 24 hpi (all p values < 0.05).ConclusionTrivalent PPrV confers protection against pneumococcal AOM in an infant murine model.     

A commercial PCV2a-based vaccine significantly reduces PCV2b transmission in experimental conditions

Transmission characteristics of PCV2 have been compared between vaccinated and non-vaccinated pigs in experimental conditions. Twenty-four Specific Pathogen Free (SPF) piglets, vaccinated against PCV2 at 3 weeks of age (PCV2a recombinant CAP protein-based vaccine), were inoculated at 15 days post-vaccination with a PCV2b inoculum (6 ⋅ 10⁵ TCID₅₀), and put in contact with 24 vaccinated SPF piglets during 42 days post-inoculation. Those piglets were shared in six replicates of a contact trial involving 4 inoculated piglets mingled with 4 susceptible SPF piglets. Two replicates of a similar contact trial were made with non-vaccinated pigs. Non vaccinated animals received a placebo at vaccination time and were inoculated the same way and at the same time as the vaccinated group. All the animals were monitored twice weekly using quantitative real-time PCR and ELISA for serology until 42 days post-inoculation. The frequency of infection and the PCV2 genome load in sera of the vaccinated pigs were significantly reduced compared to the non-vaccinated animals. The duration of infectiousness was significantly different between vaccinated and non-vaccinated groups (16.6 days [14.7;18.4] and 26.6 days [22.9;30.4] respectively). The transmission rate was also considerably decreased in vaccinated pigs (β = 0.09 [0.05–0.14] compared to β = 0.19 [0.11–0.32] in non-vaccinated pigs). This led to an estimated reproduction ratio of 1.5 [95% CI 0.8 – 2.2] in vaccinated animals versus 5.1 [95% CI 2.5 – 8.2] in non-vaccinated pigs when merging data of this experiment with previous trials carried out in same conditions.     

Genotypically distinct strains of Leishmania major display diverse clinical and immunological patterns in BALB/c mice

Infection with Leishmania major species is endemic in many provinces of Iran. Isolates from four endemic areas located in north (Damghan), center (Kashan), west (Dehloran), and south (Shiraz) of country which showed major distinctive polymorphism by RAPD-PCR method were evaluated. Isolates were inoculated to different groups of BALB/c mice and their clinical and immunological status was compared. Lesion size, parasite burden and T cell phenotype in lymph node (LN), and cytokine secretion in the culture of LN mononuclear cells were determined. The results showed the lowest and highest lesion sizes in mice infected by Shiraz strain (3.02 ± 0.52 mm) and Kashan strain (5.20 ± 0.45), respectively, 8 weeks after inoculation. No significant difference was observed between other strains. The parasite burden was significantly lower in lymph node of mice infected with strain of Damghan (1.51 × 10⁷) than Kashan (3.60 × 10⁹) and Shiraz (7.08 × 10⁹) strains, 8 weeks post-infection. However, Dehloran strain showed intermediate load of viable parasites (1.51 × 10⁹) in LN, 8 weeks post-infection. High ratios of IFN-γ/IL-4 were shown in mice inoculated by strain of Dehloran (3.17) and Damghan (2.66), but not in mice infected by other strains, 8 weeks post-infection. The highest and lowest ratios of CD4⁺/CD8⁺ T cells were found in LN cells of mice infected with Kashan (1.82) and Dehloran (1.00) strains, respectively. Results indicate that the lowest and intermediate loads of parasites induced by Damghan and Dehloran strains along with higher ratio of IFN-γ/IL-4 produced by both strains in LN of inoculated mice suggest that these strains have the capacity to shift the immune responses to a predominant Th1 response after 8 weeks infection in BALB/c mice and might be the ideal strains for vaccine studies and development of candidate vaccine against leishmaniasis.     

Factors related to vaccine uptake by young adult women in the catch-up phase of the National HPV Vaccination Program in Australia: Results from an observational study

BackgroundAustralia commenced a publically-funded, National Human Papillomavirus (HPV) Vaccination Program in 2007 with a two year catch-up phase for females aged 12–26 years.ObjectiveTo identify the factors associated with the uptake of the HPV vaccine (which has a recommended 3-dose schedule in Australia) by young adult women vaccinated by general practitioners and community-based programs within the catch-up phase.Methods1139 women who were eligible to receive the free HPV vaccine during the catch-up period were recruited in 2008–2009 (age 20–29 years at recruitment), in New South Wales, after having a normal (negative) cervical smear result recorded on the NSW Pap Test Register. Participants completed a self-administered questionnaire providing information on vaccination status, and sociodemographic and other factors.ResultsOverall, 880 (77%) women reported receiving ≥1 dose of the vaccine and 777 women (68%) reported receiving ≥2 doses. In multivariable analysis (adjusting for the period for which each woman was eligible for free HPV vaccination), uptake of ≥1 dose of the vaccine was significantly associated with being born in Australia (p < 0.01), being single (p = 0.02), being nulliparous (p < 0.01), living in a higher socioeconomic status area (p-trend = 0.03), living in more remote areas (p = 0.03), drinking alcohol (p < 0.01) and using hormonal contraceptives (p < 0.01). Although vaccinated women were more likely to have fewer sexual partners than unvaccinated women (p-trend = 0.02), they were also more likely to report a prior sexually transmitted infection (STI) (p = 0.03). Similar factors were associated with receiving ≥2 doses.ConclusionsIn this group, women living in higher socioeconomic status areas were more likely to be vaccinated against HPV in the catch-up phase of the national program. Although vaccinated women tended to have fewer sexual partners, they also reported prior STIs, which may be a marker of increased risk of prior exposure to HPV. The findings of this study reinforce the continuing need to prioritise equitable delivery of vaccination to various population subgroups.     

A commercial porcine circovirus (PCV) type 2a-based vaccine reduces PCV2d viremia and shedding and prevents PCV2d transmission to naïve pigs under experimental conditions

Porcine circovirus type 2 (PCV2) vaccination has been effective in protecting pigs from clinical disease and today is used extensively. Recent studies in vaccinated populations indicate a major PCV2 genotype shift from the predominant PCV2 genotype 2b towards 2d. The aims of this study were to determine the ability of the commercial inactivated PCV2a vaccine Circovac® to protect pigs against experimental challenge with a 2013 PCV2d strain and prevent transmission. Thirty-eight pigs were randomly divided into four groups with 9–10 pigs per group: NEG (sham-vaccinated, sham-challenged), VAC (PCV2a-vaccinated, sham-challenged), VAC + CHAL (PCV2a-vaccinated and PCV2d-challenged), and CHAL (sham-vaccinated, PCV2d-challenged). Vaccination was done at 3 weeks of age using Circovac® according to label instructions. The CHAL and VAC + CHAL groups were challenged with PCV2d at 7 weeks of age and all pigs were necropsied 21 days post-challenge (dpc). The VAC-CHAL pigs seroconverted to PCV2 by 21 days post vaccination (dpv). At PCV2d challenge on 28 dpv, 3/9 VAC and 1/9 VAC + CHAL pigs were seropositive. NEG pigs remained seronegative for the duration of the study. Vaccination significantly reduced PCV2d viremia (VAC + CHAL) at dpc 14 and 21, PCV2d fecal shedding at dpc 14 and 21 and PCV2d nasal shedding at dpc 7, 14 and 21 compared to CHAL pigs. Vaccination significantly reduced mean PCV2 antigen load in lymph nodes in VAC + CHAL pigs compared to CHAL pigs. When pooled serum or feces collected from VAC + CHAL and CHAL pigs at dpc 21 were used to expose single-housed PCV2 naïve pigs, a pooled fecal sample from CHAL pigs contained infectious PCV2 whereas this was not the case for VAC + CHAL pigs suggesting reduction of PCV2d transmission by vaccination. Under the study conditions, the PCV2a-based vaccine was effective in reducing PCV2d viremia, tissue loads, shedding and transmission indicating that PCV2a vaccination should be effective in PCV2d-infected herds.     

Effect of seasonal vaccination on the selection of influenza A/H3N2 epidemic variants

The effect of vaccination on the dynamics of influenza virus variants remains largely unknown in humans, unlike in poultry. In this study, we compared influenza hemagglutinin (HA) gene sequences isolated from vaccinated and unvaccinated populations with the yearly vaccine strains. In total, 181 influenza A/H3N2 virus samples isolated from 82 vaccinated and 99 unvaccinated patients (2011–15, four Japanese influenza seasons) were genetically analyzed using a next-generation sequencer. Amino acid (AA) differences from corresponding vaccine strains were found in 74 of 329 HA1 sites. There was a maximum of four AA differences within the epitopes in the former three seasons (2011–14) and fifteen in the latter season (2014–15). Deviation to a greater number of AA differences was found more significantly in the isolates from vaccinated patients as compared to unvaccinated patients (P = 0.0005 in 2011–14; P = 0.0096 in 2014–15). AA difference rates within epitopes were also significantly higher in the isolates from vaccinated patients than from unvaccinated patients (2.64% vs. 2.14% for 2011–14, P = 0.033; 7.78% vs. 6.59% for 2014–15, P = 0.058). The AA differences at seven sites (48I-278K, 128A-142G, 145S, 158K, and 193S) became dominant in the following seasons. In all of these sites, the dominance was retained during the mismatch of isolates with the vaccine strains and was lost after vaccine match. Our data suggest that in humans, immune pressure induced by vaccination works to select influenza variants genetically distant from vaccine strains.     

Vaccination of koalas with a prototype chlamydial vaccine is safe,does not increase the incidence of lymphoma-related disease and maybe associated with increased lifespan in captive koalas

ObjectivesTo assess the impact of Chlamydia vaccination on survival of captive koalas, and to compare the incidence of lymphomas and neoplasias between vaccinated and unvaccinated koalas.MethodsSurvival analysis using Cox and Weibull regressions on 54 vaccinated and 52 matched unvaccinated koalas, and chi-square contingency table for incidence of lymphomas/neoplasias.ResultsVaccination was found to have a significant positive effect on koala lifespan (P = 0.03), with vaccinated koalas having a median lifespan of 12.25 years compared to 8.8 years for unvaccinated ones. The effect of sex on lifespan was not significant (P = 0.31). The risk ratio of unvaccinated over vaccinated koalas was 2.2 with both Cox and Weibull regressions. There was no association between the incidence of lymphoma/neoplasias and vaccination status (P = 0.33).ConclusionsKoalas vaccinated with a prototype Chlamydia vaccine may live longer than unvaccinated ones. There was no known Chlamydia infection among koalas, so our interpretation is that vaccination may have boosted the innate and adaptive immune systems to protect against a wide spectrum of bacteria, fungi and parasites. Vaccinated koalas did not show negative physiological effects of the vaccine, for example, the frequency of deaths due to lymphomas/neoplasias was the same in both vaccinated and unvaccinated animals.     

Meningococcal C conjugate age-dependant long-term loss of effectiveness

IntroductionAlthough different epidemiological studies have assessed meningococcal C conjugate vaccine effectiveness within 1 and >1 year since vaccination, none of them evaluated long-term effectiveness. In order to assess if epidemiological data correlates with the findings described in seroprevalence studies we evaluated long-term vaccine effectiveness over time, up to 10 years since vaccination.MethodsCases targeted by vaccination programs and notified to the Spanish Surveillance System between 2001 and 2013 were included in the study. Vaccine effectiveness was estimated using the screening method. Relationship between vaccine effectiveness and time since vaccination was explored using point estimates, simple logistic regression or restricted cubic splines logistic regression model for all and for those vaccinated at <1, 1–11 and at 12–19 years of age.ResultsFrom 345 confirmed cases reported in the period and targeted by vaccination programs, 125 (36.23%) were vaccine failures. Proportion of vaccine failures decreased with age of vaccination: 63.97% at <1 year; 36.84% at 1–11 years; and 3.88% at 12–19 years. Using the best model for each group, vaccine effectiveness decreased from 99.12% to 90.85% (%change = −8.3%) for all; from 99.04% to 48.60% (%change = −50.9%) for those vaccinated at <1 years and from 99.45% to 90.18% (%change = −9.3%) for those vaccinated at 1–11 years after 10 years since vaccination. For those vaccinated at 12–19 years no changes were observed in vaccine effectiveness after 10 years (p = 0.968).ConclusionsAfter 10 years, vaccine effectiveness decreased by 50% in those vaccinated at <1 year, while those vaccinated with one dose at 12–19 years showed no changes. Vaccine failures occurred early after vaccination and more frequently in those vaccinated at younger ages. Vaccination at ≥12 years seems to be related to a low number of vaccine failures and a higher and endurable protection over time.