Protective Effect Of Vaccine Research Articles

Evaluation of vaccines against enteric infections: a clinical and public health research agenda for developing countries

Enteric infections are a major cause of morbidity and mortality in developing countries. To date, vaccines have played a limited role in public health efforts to control enteric infections. Licensed vaccines exist for cholera and typhoid, but these vaccines are used primarily for travellers; and there are two internationally licensed vaccines for rotavirus, but they are mainly used in affluent countries. The reasons that enteric vaccines are little used in developing countries are multiple, and certainly include financial and political constraints. Also important is the need for more cogent evidence on the performance of enteric vaccines in developing country populations. A partial inventory of research questions would include: (i) does the vaccine perform well in the most relevant settings? (ii) does the vaccine perform well in all epidemiologically relevant age groups? (iii) is there adequate evidence of vaccine safety once the vaccines have been deployed in developing countries? (iv) how effective is the vaccine when given in conjunction with non-vaccine cointerventions? (v) what is the level of vaccine protection against all relevant outcomes? and (vi) what is the expected population level of vaccine protection, including both direct and herd vaccine protective effects? Provision of evidence addressing these questions will help expand the use of enteric vaccines in developing countries.

Circumsporozoite-Specific T Cell Responses in Children Vaccinated with RTS,S/AS01E and Protection against P falciparum Clinical Malaria

BackgroundRTS,S/AS01E is the lead candidate pre-erythrocytic malaria vaccine. In Phase IIb field trials the safety profile was acceptable and the efficacy was 53% (95%CI 31%–72%) for protecting children against clinical malaria caused by P. falciparum. We studied CS-specific T cell responses in order to identify correlates of protection.Methods and FindingsWe used intracellular cytokine staining (for IL2, IFNγ, and TNFα), ex-vivo ELISPOTs (IFNγ and IL2) and IFNγ cultured ELISPOT assays to characterize the CS-specific cellular responses in 407 children (5–17 months of age) in a phase IIb randomized controlled trial of RTS,S/AS01E (NCT00380393). RTS,S/ AS01E vaccinees had higher frequencies of CS-specific CD4+ T cells producing IFNγ, TNFα or IL2 compared to control vaccinees. In a multivariable analysis TNFα+ CD4+ T cells were independently associated with a reduced risk for clinical malaria among RTS,S/AS01E vaccinees (HR = 0.64, 95%CI 0.49–0.86, p = 0.002). There was a non-significant tendency towards reduced risk among control vaccinees (HR = 0.80, 95%CI 0.62–1.03, p = 0.084), albeit with lower CS-specific T cell frequencies and higher rates of clinical malaria. When data from both RTS,S/AS01E vaccinees and control vaccinees were combined (with adjusting for vaccination group), the HR was 0.74 (95%CI 0.62–0.89, p = 0.001). After a Bonferroni correction for multiple comparisons (n-18), the finding was still significant at p = 0.018. There was no significant correlation between cultured or ex vivo ELISPOT data and protection from clinical malaria. The combination of TNFα+ CD4+ T cells and anti-CS antibody statistically accounted for the protective effect of vaccination in a Cox regression model.ConclusionsRTS,S/AS01E induces CS-specific Th1 T cell responses in young children living in a malaria endemic area. The combination of anti-CS antibody concentrations titers and CS-specific TNFα+ CD4+ T cells could account for the level of protection conferred by RTS,S/AS01E. The correlation between CS-specific TNFα+ CD4+ T cells and protection needs confirmation in other datasets.

Effects of Vaccination against Pandemic (H1N1) 2009 among Japanese Children

To the Editor: We report findings from a household-based study on the protective effects of vaccination against pandemic (H1N1) 2009 among Japanese children. In Japan, prioritized vaccination started in October 2009, focusing on health care workers, pregnant women, persons with underlying diseases, and children 1–9 years of age. Only nonadjuvant split vaccines (inactivated) produced by 4 manufacturers (Denka Seiken, Tokyo, Japan; Kaketsuken, Kumamoto-shi, Japan; Kitasato, Tokyo, Japan; and Biken, Suita-shi, Japan) were used by the end of January 2010 (1). Because the protective effects of vaccination at the individual level are best measured by household data (2), we conducted a retrospective household survey involving 1,614 nonrandomly sampled households (i.e., based on area sampling of households across Japan, according to the regional population size, with a total of 6,356 household members), in which the earliest cases were diagnosed from October 2009 to mid-February 2010. Our study aimed to assess vaccine-induced reductions in susceptibility and infectiousness among children by using the household secondary attack rate. Influenza cases were defined as confirmed cases (i.e., diagnosed by real-time PCR) or influenza-like illness (ILI) cases (i.e., in febrile patients [>37.5°C] with cough and/or sore throat). The cases had to meet the following inclusion criteria for analyses: 1) index case-patient and exposed persons in households were healthy children 1–9 years of age (households with 28 days before illness onset (if index case-patient) or exposure (if not index case- patient). In total, 251 children met the above criteria, comprising 109 index case-patients and 133 unvaccinated and 9 vaccinated exposed persons. The mean age was 6.4 ± 2.1 SD years. Among the 251 children, 15 (6.0%) had been vaccinated, and 169 (67.3%) had received a diagnosis of influenza. Confirmed cases accounted for 17.8% (30/169) of cases; 21 patients were the index case-patients in individual households. The mean age of patients with confirmed diagnoses was 6.5 ± 2.0 SD years and did not differ significantly from the ILI patients. Let SARij represent the household secondary attack rate (SAR) with vaccination statuses of the index patient j and exposed persons i (where i or j is 0 or 1 for unvaccinated or vaccinated, respectively), and let b represent both groups. Among 133 exposed unvaccinated children, ILI developed in 59, yielding an SAR0b of 44.4%. Among 9 exposed vaccinated children, ILI developed in 1 child, yielding an SAR1b of 11.1%. The difference between these SARs was marginally significant (p = 0.08 by Fisher exact test), and the susceptibility reduction was 1 – SAR1b/SAR0b = 75.0% (95% confidence interval [CI] –60.5% to 96.1%). Considering only exposures caused by unvaccinated first patients, SAR00 and SAR10 were 44.7% (59/132) and 0% (0/4), respectively. When the first patients with ILI in households were unvaccinated, ILI was observed in 59 of 136 children, yielding an SARb0 of 43.4%. Among 6 exposures caused by vaccinated first patients, ILI developed in 1 person, yielding an SARb1 of 16.7%. Although not significant (p = 0.40), the reduction in infectiousness by vaccination was estimated to be 1 – SARb1/SARb0 = 61.6% (95% CI –132.3% to 93.6%). The SAR01 was 0% (i.e., 1 exposure to an unvaccinated person caused by a vaccinated first patient did not result in influenza). Limiting the definition of influenza to confirmed cases, all 8 exposures to vaccinated persons did not result in influenza, and SAR0b and SAR1b were 10.8% and 0%, respectively. Similarly, all 5 exposures caused by vaccinated first patients did not result in confirmed cases, and SARb0 and SARb1 were 10.5% and 0%, respectively. Although the CIs of the estimates included zero because of the small sample size, the expected reductions in susceptibility and infectiousness were 75.0% and 61.6%, respectively, which is consistent with findings from a meta-analysis of vaccine efficacy against seasonal influenza (9). Two limitations must be noted, namely, estimates based on nonrandom samples and a case definition that relied on symptoms of case-patients. The former point cannot be explicitly addressed by a retrospective study design, but we enforced strict inclusion criteria for analyses and limited our study to healthy children. Accounting for the latter point (e.g., serologic diagnosis to capture symptomatic and asymptomatic cases) could yield slightly higher estimates than ours, provided that vaccination reduces the probability of clinical illness if infection occurs. Thus, despite these limitations and a critical need for further studies that include estimations of effectiveness (10), our results provide insight into the effects of vaccination in reducing risks for infection and clinical attack among children exposed to pandemic (H1N1) 2009 virus in their households.

Mumps Complications and Effects of Mumps Vaccination, England and Wales, 2002–2006

We analyzed data from hospital admissions and enhanced mumps surveillance to assess mumps complications during the largest mumps outbreak in England and Wales, 2004–2005, and their association with mumps vaccination. When compared with nonoutbreak periods, the outbreak was associated with a clear increase in hospitalized patients with orchitis, meningitis, and pancreatitis. Routine mumps surveillance and hospital data showed that 6.1% of estimated mumps patients were hospitalized, 4.4% had orchitis, 0.35% meningitis, and 0.33% pancreatitis. Enhanced surveillance data showed 2.9% of mumps patients were hospitalized, 6.1% had orchitis, 0.3% had meningitis, and 0.25% had pancreatitis. Risk was reduced for hospitalization (odds ratio [OR] 0.54, 95% confidence interval [CI] 0.43–0.68), mumps orchitis (OR 0.72, 95% CI 0.56–0.93) and mumps meningitis (OR 0.28, 95% CI 0.14–0.56) when patient had received 1 dose of measles, mumps, and rubella vaccine. The protective effect of vaccination on disease severity is critical in assessing the total effects of current and future mumps control strategies.

Factors Associated With Within-Herd Transmission of Serotype A Foot-and-Mouth Disease Virus in Cattle, During the 2001 Outbreak in Argentina: A Protective Effect of Vaccination

Argentina suffered an extensive foot-and-mouth disease (FMD) epidemic between July 2000 and January 2002, 3 months after obtaining the official FMD-free without vaccination status conferred by the World Organization for Animal Health. This is one of the largest FMD epidemics controlled by implementation of a systematic mass vaccination campaign in an FMD-free country. In 2000, 124 herds were reported as FMD positive, 2394 herds in 2001 and one in January 2002; the total number of cattle herds in the country at that time was approximately 230 000. Estimates of FMD transmission are important to understand the dynamics of disease spread and for estimating the value for the parameterization of disease transmission models, with the ultimate goals of predicting its spread, assessing and designing control strategies, conducting economic analyses and supporting the decision-making process. In this study, the within-herd coefficient of transmission, β, was computed for herds affected in the 2001 FMD epidemic and categorized as low or high based on the median value of β. A logistic regression model was fitted to identify factors significantly associated with high values of β. Results suggested that the odds of having a high within-herd transmission were significantly associated with time from initial herd infection to disease detection, date of report, vaccination, and time from initial herd infection to herd vaccination. Results presented in this study demonstrate, in quantifiable terms, the protective impact of vaccination in reducing FMD transmission in infected herds. These results will be useful for the parameterization of epidemiological models aimed at quantifying the impact of vaccination and for the design and implementation of FMD emergency vaccination strategies in face of an epidemic.

BCG vaccination and allergy: A systematic review and meta-analysis

There is conflicting evidence on whether BCG vaccination might represent an effective primary preventative strategy against the development of allergic sensitization and disease. We sought to systematically review the relationship between BCG vaccination and the risk of sensitization, eczema/atopic dermatitis, allergic rhinoconjunctivitis, asthma, and other allergic conditions, such as food allergy and anaphylaxis. Four international databases were searched for published epidemiologic or interventional studies. Additional online study databases were searched and vaccine manufacturers and a panel of international experts were contacted in an attempt to locate unpublished or ongoing studies. Quality assessment was undertaken by using internationally established criteria. Meta-analyses were undertaken by using fixed- or random-effects modeling. Funnel plots were used to assess for the risk of publication bias. We identified 767 articles, of which 17 satisfied our inclusion criteria; there was only 1 randomized controlled trial, with the remaining studies being epidemiologic investigations. Meta-analyses did not show any protective effect of vaccination against the risk of sensitization, as judged by specific IgE tests (odds ratio [OR], 1.31; 95% CI, 1.07-1.60) or skin prick testing (OR, 0.87; 95% CI, 0.67-1.13); the risk of atopic eczema/dermatitis (OR, 0.84; 95% CI, 0.64-1.09); or the risk of allergic rhinoconjunctivitis (OR, 1.07; 95% CI, 0.89-1.28). BCG vaccination was associated with a protective effect against the risk of asthma (OR, 0.73; 95% CI, 0.56-0.95), although this might be explained by publication bias. BCG vaccination is unlikely to be associated with protection against the risk of allergic sensitization and disease. The observed possible benefit in relation to the development of asthma is unlikely to be due to allergic sensitization.

Impact of vaccinating boys and men against HPV in the United States

We assessed the public health impact and value of vaccinating boys and men with the quadrivalent HPV vaccine in the United States. We used mathematical population models, accounting for both the direct and indirect protective effects of vaccination. Inputs for the models were obtained from public data sources, published literature, and analyses of clinical trial data. Compared with a program of vaccinating girls and women only, including boys and men 9–26 years of age would further decrease the cumulative mean number of genital wart cases, cervical intraepithelial neoplasia 2/3 cases, cancer cases, and cancer deaths by 5,146,000, 708,000, 116,000, and 40,000, respectively, within 100 years. The mean cost-effectiveness ratio (2008 US $) of this strategy was $25,700 (range: 13,600–48,800) per QALY gained if vaccination protects against all HPV 6/11/16/18-associated diseases, and $69,000 (range: 37,700–152,300)/QALY if it only protects against diseases currently in the vaccine indication. Vaccinating boys and men age 9–26 against all HPV 6/11/16/18-associated diseases provides substantial public health benefits and is cost-effective at commonly cited thresholds.

Efficacy of DNA vaccines carrying Eimeria acervulina lactate dehydrogenase antigen gene against coccidiosis

The efficacies of DNA vaccines encoding either Eimeria acervulina lactate dehydrogenase (LDH) antigen or a combination of LDH antigen and chicken IL-2 or IFN-γ were evaluated against chicken coccidiosis. Three vaccine plasmids pVAX-LDH, pVAX-LDH-IFN-γ and pVAX-LDH-IL-2 were constructed using the eukaryotic expression vector pVAX1. Expressions of proteins encoded by plasmids DNA in vivo were detected by reverse transcription-polymerase chain reaction (RT-PCR) and western blot assay. Average body weight gain, oocyst output, survival rate and lesion scores were measured to evaluate the protective effects of vaccination on challenge infection. The results showed that DNA vaccines could obviously alleviate body weight loss, duodenal lesions, oocyst output and enhance oocyst decrease ratio. Anti-coccidial indexes (ACIs) of pVAX-LDH-IFN-γ and pVAX-LDH-IL-2 groups were higher than that of other groups. Flow cytometric analysis of T lymphocytes in spleen and cecal tonsil demonstrated that DNA vaccines had significantly increased percentages of CD3 + T cells compared with pVAX1 alone or TE buffer. The results provided the first proof that DNA vaccine carrying E. acervulina LDH antigen gene induced protective immunity against homologous infection and its effect could be enhanced by co-expression of chicken IL-2 or IFN-γ.

Protective effects of vaccines against Bordetella parapertussis in a mouse intranasal challenge model

Bordetella parapertussis causes typical whooping cough, as does Bordetella pertussis. However, current commercial vaccines are ineffective against B. parapertussis. In an effort to develop vaccines that are effective in protecting against both B. pertussis and B. parapertussis, we examined the protective effects of vaccines prepared from whole-cells and from recombinant proteins derived from B. parapertussis in a mouse intranasal challenge model. We confirmed current pertussis vaccines did not induce protective immunity against B. parapertussis in the mouse model. A whole-cell vaccine prepared from B. parapertussis induced protective immunity against B. parapertussis but not against B. pertussis, suggesting a combination of a current pertussis vaccine with a whole-cell parapertussis vaccine might prevent whooping cough caused by both species of Bordetella. We also found that filamentous hemagglutinin was a protective antigen of B. parapertussis. Our observations should lead to the development of new pertussis vaccines that can control the two prevalent forms of whooping cough.

Intraperitoneal and intra-nasal vaccination of mice with three distinct recombinantNeospora caninumantigens results in differential effects with regard to protection against experimental challenge withNeospora caninumtachyzoites

Recombinant NcPDI(recNcPDI), NcROP2(recNcROP2), and NcMAG1(recNcMAG1) were expressed in Escherichia coli and purified, and evaluated as potential vaccine candidates by employing the C57Bl/6 mouse cerebral infection model. Intraperitoneal application of these proteins suspended in saponin adjuvants lead to protection against disease in 50% and 70% of mice vaccinated with recNcMAG1 and recNcROP2, respectively, while only 20% of mice vaccinated with recNcPDI remained without clinical signs. In contrast, a 90% protection rate was achieved following intra-nasal vaccination with recNcPDI emulsified in cholera toxin. Only 1 mouse vaccinated intra-nasally with recNcMAG1 survived the challenge infection, and protection achieved with intra-nasally applied recNcROP2 was at 60%. Determination of cerebral parasite burdens by real-time PCR showed that these were significantly reduced only in recNcROP2-vaccinated animals (following intraperitoneal and intra-nasal application) and in recNcPDI-vaccinated mice (intra-nasal application only). Quantification of viable tachyzoites in brain tissue of intra-nasally vaccinated mice showed that immunization with recNcPDI resulted in significantly decreased numbers of live parasites. These data show that, besides the nature of the antigen, the protective effect of vaccination also depends largely on the route of antigen delivery. In the case of recNcPDI, the intra-nasal route provides a platform to generate a highly protective immune response.

Incorporation of NKT Cell-Activating Glycolipids Enhances Immunogenicity and Vaccine Efficacy of Mycobacterium bovis Bacillus Calmette-Guérin

The attenuated strain of Mycobacterium bovis known as bacille Calmette-Guérin (BCG) has been widely used as a vaccine for prevention of disease by Mycobacterium tuberculosis, but with relatively little evidence of success. Recent studies suggest that the failure of BCG may be due to its retention of immune evasion mechanisms that delay or prevent the priming of robust protective cell-mediated immunity. In this study, we describe an approach to enhance the immunogenicity of BCG by incorporating glycolipid activators of CD1d-restricted NKT cells, a conserved T cell subset with the potential to augment many types of immune responses. A method was developed for stably incorporating two forms of the NKT cell activator alpha-galactosylceramide into live BCG organisms, and the impact of this on stimulation of T cell responses and protective antimycobacterial immunity was evaluated. We found that live BCG containing relatively small amounts of incorporated alpha-galactosylceramide retained the ability to robustly activate NKT cells. Compared with immunization with unmodified BCG, the glycolipid-modified BCG stimulated increased maturation of dendritic cells and markedly augmented the priming of Ag-specific CD8(+) T cells responses. These effects were correlated with improved protective effects of vaccination in mice challenged with virulent M. tuberculosis. These results support the view that mycobacteria possess mechanisms to avoid stimulation of CD8(+) T cell responses and that such responses contribute significantly to protective immunity against these pathogens. Our findings raise the possibility of a simple modification of BCG that could yield a more effective vaccine for control of tuberculosis.

Experimental IPN virus infection of Atlantic salmon parr; recurrence of IPN and effects on secondary bacterial infections in post-smolts

Infectious pancreatic necrosis (IPN) in Atlantic salmon ( Salmo salar L.) is a considerable problem in the Norwegian and Scottish fish farming industry. The disease is a main contributor to the post-smolt mortalities often observed in the first weeks after transfer to seawater. Asymptomatic carriers of infectious pancreatic necrosis virus (IPNV) are common, but the implications this has for the fish are largely unknown. In an experiment which lasted for 10 months, we aimed at investigating if vaccination, smoltification and seawater transfer may affect an IPNV carrier condition established in freshwater, and the possibility of reappearance of IPN in post-smolts. Vice versa, we wanted to see if this IPNV carrier condition could affect the protective effects of vaccines against bacterial pathogens, and the outcome of secondary bacterial infections. No changes in the IPNV carrier condition were registered during the period in freshwater, however a reactivation of the carrier condition occurred after transfer to seawater and 24% of the unvaccinated fish died due to IPN. The vaccine offered some unspecific protection against recurrence, and significantly fewer fish, 7%, died in the vaccinated group. In the challenge experiments with Aeromonas salmonicida and Vibrio salmonicida 15 weeks and 28 weeks after vaccination, respectively, the vaccine offered the same good protection against the bacterial pathogens in both IPNV carriers and in non-carriers. In the unvaccinated groups the time point of challenge with A. salmonicida concurred with the onset of IPN mortality in the IPNV carrier group, and significantly more fish in this group died compared to the control fish. The V. salmonicida challenge was performed several weeks after the IPN mortality had stopped. Mortality levels reached over 90% in both unvaccinated groups, but the fish started to die earlier and mortalities were significantly higher at day 8 till 12 after challenge in the IPNV carrier group, indicating that the fish could still be affected several weeks after the recurrence of IPNV. An asymptomatic carrier condition did not seem to have negative impact on the Atlantic salmon during the freshwater stage. However, we have demonstrated that an IPNV carrier state implies a risk of recurrence resulting in IPN mortality after seawater transfer. An oil-adjuvanted vaccine without IPNV antigens offered unspecific and significant protection against recurrence, and at the same time the specific protective effects against the bacterial pathogens were not impaired in the carrier fish.

Influence of host genetic variation on rubella-specific T cell cytokine responses following rubella vaccination

The variability of immune response modulated by immune response gene polymorphisms is a significant factor in the protective effect of vaccines. We studied the association between cellular (cytokine) immunity and HLA genes among 738 schoolchildren (396 males and 342 females) between the ages of 11 and 19 years, who received two doses of rubella vaccine (Merck). Cytokine secretion levels in response to rubella virus stimulation were determined in PBMC cultures by ELISA. Cell supernatants were assayed for Th1 (IFN-γ, IL-2, and IL-12p40), Th2 (IL-4, IL-5, and IL-10), and innate/proinflammatory (TNF-α, GM-CSF, and IL-6) cytokines. We found a strong association between multiple alleles of the HLA-DQA1 (global p-value 0.022) and HLA-DQB1 (global p-value 0.007) loci and variations in rubella-specific IL-2 cytokine secretion. Additionally, the relationships between alleles of the HLA-A (global p-value 0.058), HLA-B (global p-value 0.035), and HLA-C (global p-value 0.023) loci and TNF-α secretion suggest the importance of HLA class I molecules in innate/inflammatory immune response. Better characterization of these genetic profiles could help to predict immune responses at the individual and population level, provide data on mechanisms of immune response development, and further inform vaccine development and vaccination policies.

Association of influenza vaccination with reduced risk of venous thromboembolism

Influenza vaccination can reduce the risk of cardiovascular events in patients with coronary heart disease, but its impact on the risk of venous thromboembolism (VTE) has not been studied. It was the aim of this study to investigate whether influenza vaccination reduces the risk of VTE. We conducted a case-control study involving 1,454 adults enrolled in 11 French centers between 2003 and 2007, comprising 727 consecutive cases with a first documented episode of VTE and 727 age- and sex-matched controls. In the case and control groups 202 (28.2%) and 233 (32.1%) subjects, respectively, had been vaccinated against influenza during the previous 12 months. After multivariate regression analysis, the odds ratios (OR) for VTE associated with vaccination were 0.74 (95% confidence interval [CI], 0.57-0.97) and 0.52 (95% CI, 0.32-0.85), respectively, for the whole population and for subjects aged 52 years or less. The protective effect of vaccination was similar for deep venous thrombosis (OR 0.9, 95% CI, 0.60-1.35) and pulmonary embolism (OR 0.71, 95% CI, 0.53-0.94) and for both provoked (OR 0.71, 95% CI, 0.53-0.97) and unprovoked VTE (OR 0.85, 95% CI, 0.59-1.23). This case-control study suggests that influenza vaccination is associated with a reduced risk of VTE.

Serological Studies of Infectious Bronchitis Vaccines against Japanese Field Isolates of Homologous and Heterologous Genotypes

The genetic diversity of the partial S1 gene involving the hyper variable region for infectious bronchitis (IB) vaccine strains in Japan were compared with those of IB virus isolated from the field in Japan. Field isolates have mainly been classified into three major genotypes, JP-I, JP-II and JP-III, since 2003; however, the 4/91 genotype was detected from recent field isolates in Japan. The virus neutralization (VN) activity with vaccine immunized serum was investigated to evaluate the protective effects of vaccines against Japanese field isolates. In the results of the VN test, antiserum immunized with the GN and C78 (JP-I), TM-86w and Miyazaki (JP-II) and 4/91 (793B) vaccine strains could neutralize a high rate of field isolates of homologous genotype (75% of field isolates of JP-I, 100% of that of JP-II and 100% of that of 793B, respectively). For field isolates of JP-III, even though there are no homologous genotype vaccine strain, some strains of JP-III were neutralized with immune serum from vaccine strains of the heterologous genotype. In this study, a correlation between serological property and genotype was found for JP-I, JP-II and 793B. Our results suggested that an effective vaccine could be predicted in accordance with the genotype of field isolates.

Inherited complement deficiencies and bacterial infections

A wide variety of bacteria are recognized by the complement system through the early components that trigger the three pathways of complement activation, leading to the release of biologically active products involved in opsonization, recruitment of phagocytes and bacterial killing. Deficiencies of complement components and regulators provide a model to understand the in vivo role of complement as a defense system against bacterial infections. An increased susceptibility to these types of infections is frequently seen in individuals with C2, C3, late component, properdin and factor I deficiencies. The identification of these deficiencies is essential for the adoption of preventive measures aimed to reduce the risk of bacterial infections. Vaccination represents the treatment of choice to protect these subjects, although further studies on a large number of C-deficient individuals are needed to prove the protective effect of vaccines.

Development of Vaccine-Based Immunotherapy for Murine Large B-Cell Lymphoma

Diffuse Large B Cell Lymphoma (DLBCL) is an aggressive form of Non-Hodgkin's Lymphoma (NHL) accounting for 40% of NHL in the United States. Current treatment options are ineffective in eliminating refractory lymphoma, which is responsible for patient relapse. Therefore, a carefully developed immunotherapeutic strategy to specifically target refractory lymphoma might be useful in improving therapy. In this study, anti-lymphoma immune outcome was evaluated in a syngeneic murine model using the aggressive and highly liver metastatic RAW117-H10 lymphoma cell line that expresses the murine leukemia virus protein gp70. Anti-lymphoma immunity was generated by immunizing Balb/c mice with two peptide-based vaccines in which a T cell epitope from gp70 (SSWDFITV) was covalently attached to the N-termini of two response-selective molecular adjuvants derived from complement component C5a: YSFKPMPLaR (EP54) and YSFKDMP(MeL)aR (EP67). In both vaccines, a protease-sensitive, double-Arg linker sequence (RR) was placed between the epitope and the EP54/EP67 molecular adjuvants: SSWDFITV-RR-YSFKPMPLaR (Vaccine 2) and SSWDFITV-RR-YSFKDMP(MeL)aR (Vaccine 3). To determine the protective effect of the EP54/EP67-containing vaccines against lymphoma growth, separate groups of Balb/c mice were administered 200 μg of Vaccine 2 or Vaccine 3 dissolved in water via intraperitoneal (100 μg) and intradermal (100 μg) injections. Following 4 weekly immunizations, the mice were intravenously transplanted with 5 × 103 RAW117-H10 cells to ascertain the protective benefit of the vaccines. The results showed Vaccines 2 and 3 providing complete protective benefit, with pre-vaccinated mice surviving greater than 235 days, whereas all control, unvaccinated animals died within 18 days of tumor inoculation. In addition to survival analysis, histopathological analysis was performed using liver sections from mice upon death, or after sacrifice following 60 days of survival, to evaluate tumor burden in the mice (See Figure 1). No tumor growth was found in livers taken from mice pre-vaccinated with Vaccines 2 and 3. Furthermore, to elucidate the mechanisms of vaccine-mediated protection against lymphoma, the frequency and functions of the immune effector cells from blood and spleens were analyzed at 72 hours following the second and fourth vaccinations using flow cytometry, T and B cell-specific mitogen proliferation assays, and lymphoma-specific cytotoxicity assays in vitro. The results of these analyses showed a significant increase in the frequency (p< 0.01) of helper and cytotoxic T cells, proliferation of both T and B cells (p< 0.05), and significant lymphoma-specific cytotoxicity (p< 0.001) compared to non-vaccinated mice. Therefore, these results demonstrate a pronounced protective effect of Vaccines 2 and 3 against lymphoma growth in mice. These results lay the foundation for further studies in testing the therapeutic efficacy of Vaccines 2 and 3 in mice pre-inoculated with lymphoma, as well as in initiating studies employing human lymphomas. In so doing, the principles underlying these molecular adjuvant-containing vaccines could eventually be translated from the mouse model to a clinical setting. [Display omitted]

Abstract 524: Influenza Vaccination Reduces The Risk Of Venous Thromboembolism

It is widely accepted that influenza vaccination reduces the risk of cardiovascular events in patients with coronary artery diseases. However, no information is available concerning the role of influenza vaccination in venous thromboembolism (VTE). Methods: A case-control study was conducted in 727 cases and 727 age and sex-matched controls from 11 centers in France (the FARIVE study). Cases were patients with a first documented episode of VTE and without any personal history of cancer within the last 5 years; controls were recruited in the same hospital and had no personal history of venous or arterial thrombosis. Results: Overall, 202 (28.2%) of cases and 233 (32.1%) of controls had influenza vaccination during the previous 12 months at the time of recruitment. Information was not available for only 12 subjects out of 1454. The crude odds ratio (OR) for VTE associated with influenza vaccination was 0.76 (95% CI 0.58–0.99). After adjustment for potential confounding variables (age, sex, inclusion date, BMI, educational levels and varicose veins), the OR for VTE associated with vaccination was 0.74 (95% CI 0.57–0.97). The protective effect of vaccination toward VTE was higher in the population below 52 years (median of age), with an OR of 0.52 (95% CI 0.32–0.85). In women below the age of 51, the crude OR for VTE associated with influenza vaccination was 0.50 (95% CI 0.24–1.05) and was significant after adjustment for confounding variables including oral contraceptives, with an OR of 0.41 (95% CI 0.19–0.92). The protective effect of vaccination was similar for different types of VTE (DVT or PE). There was no statistical differences in the protective effects when we compared provoked with unprovoked VTE events. Conclusion: This is the first study that demonstrates a protective effect of influenza vaccination in VTE. In vitro influenza induces activation of coagulation and inflammation but we cannot rule out that the protective effect of influenza vaccination was due to other unknown mechanisms, as the protective effect was similar within the different seasons of the year. Influenza vaccination may reduce the risk of VTE by 26%. This relationship between influenza vaccination and VTE and its underlying mechanism still need to be analyzed and confirmed in further studies.

Milk Production Change Following Clinical Mastitis and Reproductive Performance Compared Among J5 Vaccinated and Control Dairy Cattle

Naturally occurring cases of bovine clinical mastitis (CM) were studied among J5 vaccinates and controls on 3 commercial dairy farms. Milk production change and reproductive performance following CM were compared between the 2 groups. Among 306 controls and 251 vaccinates, there were 221 new cases of CM affecting 120 cows; 437 lactations never had a case of CM. Environmental pathogens made up 90% (159/176) of etiologic agents isolated. Change in daily milk production following CM was associated with J5 vaccination, days in milk (DIM) at onset of CM, and herd effect as well as each 2-way interaction between the 3 factors. The adjusted daily milk for 21 d following CM was 7.6kg greater among J5 vaccinates than controls; however, this protective effect of vaccination waned with increasing DIM at onset of CM. A mixed linear model with autoregressive order 1 [AR(1)] correlation structure estimated the daily milk production of any cow (whether or not she had CM) on a given DIM. Cows with CM caused by nonagalactiae streptococci, Staphylococcus aureus, Escherichia coli, or Klebsiella lost significant daily milk production for the entire lactation relative to nonmastitic cows. Another mixed linear model for only coliform CM cases (E. coli, Klebsiella, and Enterobacter) within the first 50 DIM showed milk loss for 21 d following coliform CM to be significantly less for J5 vaccinates than for controls, by 6 to 15kg per day. Cows were significantly less likely to become pregnant if they had CM caused by E. coli (42% pregnant) or Streptococcus spp. (38% pregnant), whereas 78% (342/437) of cows with no mastitis conceived. Days open (number of days from calving until pregnancy) averaged 131 d for cows with no CM and 162 d for cows that had at least one case of CM. Days until conception, days until last breeding, days open, times bred, and percentage of cows pregnant by 200 DIM were not changed with J5 vaccination. Nonetheless, an important benefit of the use of J5 bacterin appears to be reduction of the loss of daily milk production following CM, whether all cases or only those caused by coliform bacteria were considered.

Biology of Immune Responses to Vaccines in Elderly Persons

With increasing age, the human immune system undergoes characteristic changes, termed immunosenescence, which lead to increased incidence and severity of infectious diseases and to insufficient protection following vaccination. Functional defects and altered frequencies of innate and adaptive immune cells impair local responses at the site of vaccine injection, hamper the generation of primary responses to neoantigens, prevent the effective induction of memory lymphocytes, and decrease the effect of booster vaccination. As a result, antibody responses of elderly vaccinees are weaker and decline faster, and long-term protective effects of vaccination cannot be taken for granted in elderly persons. Improved vaccination strategies, new adjuvants, and new vaccines that specifically target the aged immune system will help to overcome the limitations of immunosenescence and ensure a better protection of the vulnerable elderly population.