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PubMed2005

Development and validation of puma (Felis concolor) cytokine and lentivirus real-time PCR detection systems.

Studies of immune correlates of disease outcome associate humoral immune response mediated by T-helper 2 cytokines (IL-4, IL-10) with more virulent disease relative to a cell-mediated response driven by T-helper 1 cytokines (IL-2, IFN-gamma), particularly in viral and other intra-cellular infections. Specifically, the kinetics of both human immunodeficiency virus (HIV) and feline immunodeficiency virus (FIV) infection are closely associated with Type 1 versus Type 2 cytokine profiles. Puma (Felis concolor) lentivirus (PLV) is closely related to FIV, but based on phylogenetic and clinical studies, is more ancient and less pathogenic. The aims of this study were to validate feline real-time PCR primer/probe systems for puma cytokines and PLV as sensitive, quantitative assays for use in investigations of PLV pathogenicity. We demonstrate that primer/probe systems for IL-4, IL-10, IFN-gamma, TNF-alpha, GAPDH, and the pol region of PLV-1695 amplify puma cytokines and PLV-1695 with high amplification efficiency and sensitivity. Detection of PLV-1695 provirus in experimentally inoculated domestic cats proved to be of equivalent sensitivity, specificity, and positive and negative predictive value to co-culture of one million peripheral blood mononuclear cells (PBMC). Evaluation of cytokine induction during naturally occurring PLV infection will allow insight into mechanisms of host control associated with apathogenic infection. In addition, determination of viral loads during different stages of PLV infection or in different tissues from domestic cats or pumas will further elucidate capacity of these viruses to replicate and establish infection.

Animals↗
PubMed1986

Delayed-type hypersensitivity and immunity to Salmonella typhimurium.

Studies were carried out to correlate immunity and expression of delayed-type hypersensitivity (DTH) in mice of the C3H lineage immunized with an avirulent strain of Salmonella typhimurium (strain SL3235). This strain belongs to a class of aroA- organisms which are being considered as vaccine strains for humans and veterinary use. In a systematic study, the relationship between the mouse strain and the immunizing dose of strain SL3235 on the development of protective immunity and DTH was examined. It was found that in hypersusceptible C3H/HeJ and C3HeB/FeJ mice, several doses of strain SL3235 afforded protection against intravenous challenge doses as high as 1,300 50% lethal doses. Despite these significant levels of immunity to challenge, mice of these two strains never mounted significant DTH responses following immunization with the doses of strain SL3235 tested, which spanned 3 orders of magnitude. Nonresponsiveness was not due to antigen overload, as all of the mouse strains were comparably colonized with strain SL3235 at the time of DTH elicitation. Further, it was found that the ability of responsive C3H/HeNCrlBR mice to display DTH was dependent on the immunizing dose of strain SL3235 and that a dosage could be found that resulted in increased resistance to challenge in these mice without a concomitant display of DTH. Thus, while both induction of protective immunity and DTH were vaccine dosage dependent in the responsive mouse strain (C3H/HeNCrlBR), DTH was a less sensitive measure of protective immunity than survival. Vaccine dosages ranging over three orders of magnitude failed to yield positive footpads to the Salmonella elicitin in the nonresponsive mice. The data suggest that caution should be observed in interpreting Salmonella DTH tests that are used as screens of immune status to typhoid fever in humans, as the extent of discordance between immunity and DTH in humans is unknown.

Animals↗
PubMed2005

Identifying immune traits and biobehavioral correlates: generalizability and reliability of immune responses in rhesus macaques.

Variation in immune responses over time and in different contexts presents a methodological challenge for characterizing the typical immune status of an individual. Our analyses statistically evaluated sampling strategies for optimizing the determination of an "immune trait" in studies of individual differences with nonhuman primates. Lymphocyte proliferation and natural killer cell activity were assessed on multiple occasions at 3-week intervals in male rhesus macaques for up to 1 year while they lived in undisturbed conditions. Generalizability and Monte Carlo analyses were utilized to explore the benefits of multiple evaluations and the effects of reliability on replication. There were substantial gains in reliability and stability by obtaining 4 or more immune assessments of the same individual, and the benefits continued to accrue to an optimal assessment level of 10 or more evaluations for each individual. The value of determining "immune traits" was then exemplified by demonstrating the degree to which the monkeys' handedness correlated with reliable indices of proliferative and cytolytic responses averaged over 1 year of assessment.

Analysis of Variance↗
PubMed2002

Passive transfer studies to elucidate the role of antibody-mediated protection against HIV-1.

In order to understand immune correlates of protection and to develop effective immunization strategies, it is important to know if antibodies can confer protection against HIV-1 infection or disease. The recent development of the pathogenic simian/human immunodeficiency virus (SHIV)-macaque model based on env genes from primary HIV-1 isolates permits the in vivo evaluation of anti-HIV-1 envelope glycoprotein immune responses. Using this model, we and others initially showed that passively infused antibody can protect against an intravenous SHIV-challenge. However, HIV-1 is most often transmitted across mucosal surfaces and the intravenous challenge model may not accurately predict the role of antibody in protection against mucosal exposure. We, therefore, adapted the SHIV89.6PD model to allow evaluation of anti-HIV-1 antibodies against vaginal challenge. In order to make comparisons to our prior intravenous challenge study, we used the same SHIV89.6PD stock and antibodies. Our data show that antibodies can confer protection against vaginal exposure to a pathogenic SHIV; if virus transmission occurs, their presence can ameliorate the subsequent pathogenic manifestations of virus infection. Compared to our previous intravenous challenge study, greater protection was achieved after vaginal challenge. Because the highest level of protection occurred when the most potent combinations of antibodies were used, the data confirm that in vitro neutralization assays on peripheral blood mononuclear cells (PBMC) targets cells are a relevant measure of protective antibody activity.

AIDS Vaccines↗
PubMed2005

Sustained E2 antibody response correlates with reduced peak viremia after hepatitis C virus infection in the chimpanzee.

Immune correlates of protection against hepatitis C virus (HCV) infection are not well understood. Here we investigated 2 naive and 6 immunized chimpanzees before and after intravenous challenge, 12 weeks after the last immunization, with 100 50% chimpanzee infectious doses (CID(50)) of heterologous genotype 1b HCV. Vaccination with recombinant DNA and adenovirus vaccines expressing HCV core, E1E2, and NS3-5 genes induced long-term HCV-specific antibody and T-cell responses and reduced peak viral load about 100 times compared with controls (5.91 +/- 0.38 vs. 3.81 +/- 0.71 logs, respectively). There was a statistically significant inverse correlation between peak viral loads and envelope glycoprotein 2 (E2)-specific antibody responses at the time of challenge. Interestingly, one vaccinee that had sterilizing immunity against slightly heterologous virus generated the highest level of E2-specific total and neutralizing antibody responses as well as strong NS3/NS5-specific T-cell proliferative responses. The other four vaccinees with low levels of E2-specific antibody had about 44-fold reduced peak viral loads but eventually developed persistent infections. In conclusion, vaccine-induced E2-specific antibody plays an important role in prevention from nonhomologous virus infection and may provide new insight into the development of an effective HCV vaccine.

Animals↗
PubMed2005

Priming with plasmid DNAs expressing interleukin-12 and simian immunodeficiency virus gag enhances the immunogenicity and efficacy of an experimental AIDS vaccine based on recombinant vesicular stomatitis virus.

Of the various approaches being developed as prophylactic HIV vaccines, those based on a heterologous plasmid DNA prime, live vector boost vaccination regimen appear especially promising in the nonhuman primate/simian-human immunodeficiency virus (SHIV) challenge model. In this study, we sought to determine whether a series of intramuscular priming immunizations with a plasmid DNA vaccine expressing SIVgag p39, in combination with plasmid expressed rhesus IL-12, could effectively enhance the immunogenicity and postchallenge efficacy of two intranasal doses of recombinant vesicular stomatitis virus (rVSV)-based vectors expressing HIV-1 env 89.6P gp160 and SIVmac239 gag p55 in rhesus macaques. In macaques receiving the combination plasmid DNA prime, rVSV boost vaccination regimen we observed significantly increased SIVgag- specific cell-mediated and humoral immune responses and significantly lower viral loads postintravenous SHIV89.6P challenge relative to macaques receiving only the rVSV vectored immunizations. In addition, the plasmid DNA prime, rVSV boost vaccination regimen also tended to increase the preservation of peripheral blood CD4+ cells and reduce the morbidity and mortality associated with SHIV89.6P infection. An analysis of immune correlates of protection after SHIV89.6P challenge revealed that the prechallenge SHIV-specific IFN-gamma ELISpot response elicited by vaccination and the ability of the host to mount a virus-specific neutralizing antibody response postchallenge correlated with postchallenge clinical outcome. The correlation between vaccine-elicited cell-mediated immune responses and an improved clinical outcome after SHIV challenge provides strong justification for the continued development of a cytokine-enhanced plasmid DNA prime, rVSV vector boost immunization regimen for the prevention of HIV infection.

AIDS Vaccines↗
PubMed1998

Efficacy evaluation of prime-boost protocol: canarypoxvirus-based feline immunodeficiency virus (FIV) vaccine and inactivated FIV-infected cell vaccine against heterologous FIV challenge in cats.

OBJECTIVE: To evaluate the immunogenicity and prophylactic efficacy of immunization schemes employing a recombinant canarypoxvirus ('ALVAC')-based feline immunodeficiency virus (FIV) vaccine alone or in combination with an inactivated FIV-infected cell vaccine against homologous and heterologous FIV challenges in cats. METHODS: Specific pathogen-free cats were given a total of three immunizations with subtype A vaccines and challenged 4 weeks after the final immunization with 50 median animal infectious doses (ID50) of FIV-Petaluma, a subtype A isolate. Following the initial challenge, protected cats received a second challenge with 75 ID50 of FIV-Bangston, a subtype B isolate. FIV-specific humoral and cell-mediated responses were measured to determine the immune correlates of protection. RESULTS: Two of three cats immunized with the ALVAC FIV recombinants alone were protected from homologous FIV challenge in the presence of FIV-specific cytotoxic T-lymphocyte (CTL) responses but in the absence of FIV-specific humoral responses. All three cats immunized with the ALVAC-FIV recombinant and boosted with FIV-infected cell vaccine were also protected from homologous FIV challenge in the presence of both FIV-specific CTL and humoral responses. Partial to full protection was observed in ALVAC-FIV/FIV-infected cell vaccine-immunized cats against a heterologous FIV challenge given 8 months after the initial challenge. Two out of three cats had transient infection and the remaining cat had no sign of FIV infection at a dose at which all three control cats were readily infected. CONCLUSIONS: Immunization schemes employing ALVAC-based FIV vaccines in combination with inactivated FIV-infected cell vaccine generate protective immune responses that can cross-react with FIV isolates that are genetically distinct from the vaccine strains.

Animals↗
PubMed1979

Local cholera immunity in mice: intestinal antitoxin-containing cells and their correlation with protective immunity.

Methods for light and electron microscopic identification and characterization of intestinal cholera antitoxin-containing cells (ACC) using peroxidase-labeled immunoreagent are described and used to study the ACC response in mice after immunizations with cholera toxin. Specific ACC appeared in significant numbers after two oral immunizations and increased six- to eightfold with two additional oral boosters, whereas further oral immunizations caused no additional stimulation. Intravenous immunizations had to be repeated seven times before ACC could be detected. After two oral immunizations, most of the ACC were found in the proximal part of the small intestine and no ACC were seen in the colon. This uneven distribution of ACC within the small intestine was eliminated after four oral immunizations, when ACC could also be detected in the colon. The ACC response after four oral immunizations demonstrated a peak at 4 days with far fewer cells present at 2 and 7 days. Electron microscopic studies showed that the ACC were mature plasma cells with the staining localized to the endoplasmic reticulum. Regression analysis of the relationship between the number of ACC and the magnitude of protective immunity against intestinal challenge with cholera toxin indicates a highly significant correlation (r = 0.91, P less than 0.001).

Animals↗
PubMed1987

Immunologic defects as possible causes of therapeutic failures in children with transposition of the great arteries.

Recurrent and severe infections and absence of thymic shadow in X-ray examination were observed in children with the transposition of the great arteries (TGA). Among 45 children (29 boys and 16 girls) with TGA whose age ranged from 3 days to 16 years and who were hospitalized during 1 year, infectious diarrhea was observed in 77.7% cases, urinary tract infections in 44.5%, respiratory tract infections in 42.2%, sepsis in 17.5%, and meningitis in 8.8%. Nine of the children died, sepsis was a cause of death in seven children, and there were postsurgical complications in two children. Immunologic abnormalities in children with TGA included a decreased level of T-lymphocytes and T29 degrees subpopulation, impaired mitogen-induced lymphoproliferation in vitro, and increased nitro blue tetrazolium (NBT) reduction activity of monocytes. Impaired parameters of cellular immunity correlated with worst clinical status. No disorders of humoral immunity were observed. These observations may be important for forming opinion about proper therapy and the cause of death in children with TGA.

Bacterial Infections↗
PubMed2006

Role of T lymphocyte replicative senescence in vaccine efficacy.

Immunological changes associated with aging play a major role in both the blunted responses to infections as well as to vaccines intended to prevent many of these infections. Several independent studies on immune correlates of poor vaccine responsiveness have identified a novel immune biomarker of reduced antibody response to vaccination, namely high proportions of memory CD8 T lymphocytes lacking expression of the CD28 costimulatory molecule. Research on this population of CD8(+)CD28(-) T lymphocytes has documented characteristics suggestive of replicative senescence, including inability to proliferate, reduced telomere length, and altered cytokine profiles. CD8(+)CD28(-) T lymphocytes have also been associated with suppressor functions and with early mortality in the elderly. This article discusses some of the challenges involved in custom-designing vaccines for the elderly, and suggests several immunomodulatory strategies that may enhance vaccine responsiveness in this age group.

Aging↗
PubMedDate not supplied

Immune responses of infants to infection with respiratory viruses and live attenuated respiratory virus candidate vaccines.

Respiratory viruses such as respiratory syncytial virus (RSV), the parainfluenza viruses (PIV), and the influenza viruses cause severe lower respiratory tract diseases in infants and children throughout the world. Experimental live attenuated vaccines for each of these viruses are being developed for intranasal administration in the first weeks or months of life. A variety of promising RSV, PIV-3, and influenza virus vaccine strains have been developed by classical biological methods, evaluated extensively in preclinical and clinical studies, and shown to be attenuated and genetically stable. The ongoing clinical evaluation of these vaccine candidates, coupled with recent major advances in the ability to develop genetically engineered viruses with specified mutations, may allow the rapid development of respiratory virus strains that possess ideal levels of replicative capacity and genetic stability in vivo. A major remaining obstacle to successful immunization of infants against respiratory virus associated disease may be the relatively poor immune response of very young infants to primary virus infection. This paper reviews the immune correlates of protection against disease caused by these viruses, immune responses of infants to naturally-acquired infection, and immune responses of infants to experimental infection with candidate vaccine viruses.

Child↗
PubMed2003

Immunology of viral respiratory tract infection in infancy.

Respiratory viruses such as respiratory syncytial virus (RSV), parainfluenza viruses (PIV) and the influenza viruses cause severe lower respiratory tract disease in infants and children throughout the world. We discuss the recent discovery of the epidemiologic importance of the human metapneumoviruses, first reported in 2001. Experimental live-attenuated vaccines for each of these viruses are being developed for intranasal administration in the first weeks or months of life. The immunology of these infections in humans is poorly defined but many studies are ongoing. A significant obstacle to successful immunisation of infants against respiratory-virus-associated disease early in life may be the relatively poor immune response of very young infants to primary virus infection. This paper reviews the immune correlates of protection against disease caused by these viruses, immune responses of infants to naturally acquired infection or experimental infection with candidate vaccine viruses and the genetics of susceptibility to severe disease.

Animals↗
PubMed1989

Immunogenicity and tumor protective activity of B16 melanoma vaccines.

The immunogenicity and tumor-protective activity of different vaccines were examined and compared with murine B16 melanoma. All vaccines were prepared from material shed into culture medium by B16 melanoma cells. Vaccine I was generated by concentrating the shed material. Vaccine II was partially purified by precipitating the shed material with 50% ammonium sulfate followed by sephadex G-200 column chromatography. Vaccine III was concentrated shed material that was treated with 0.5% NP-40 and then ultracentrifuged to remove transplantation antigens. Mice were immunized to equal protein concentrations of vaccines weekly for 5 weeks or to control buffer. Antibody, cellular, and tumor-protective immunity to melanoma was measured in all mice 2 weeks following the last immunization. All three vaccine preparations were immunogenic. Vaccine preparation I appeared to be the most immunogenic and the one that most consistently augmented tumor-protective immunity. Augmentation in tumor-protective immunity correlated better with increase in cellular than in humoral immunity to melanoma.

Animals↗
PubMed2003

Vaccine for AIDS and Ebola virus infection.

Ebola virus and HIV present challenges for vaccine development because natural immunity to these viruses is difficult to find, and there are no immune correlates of protection in humans. Modern molecular genetic, virologic and immune analyses have been used to rationally identify promising approaches based on animal model and human clinical studies. Improved vaccine candidates have been defined for HIV, and a promising Ebola vaccine have conferred protection in non-human primates. Further evaluation in humans will allow an assessment of their potential efficacy and point the way to the development of more successful vaccines.

AIDS Vaccines↗
PubMed1975

BCG immunopotentiation of an antitumor response: evidence for a cell-mediated mechanism.

BCG-immunopotentiated antitumor immunity was studied in a model in which irradiated murine tumor cells, mastocytoma P815, were injected into subcutaneous sites prepared by a prior injection of BCG; challenge in a distant foot-pad was used as an indicator of specific resistance. The onset of antitumor immunity correlated with the proliferation of lymph node cells draining the immunization sites and the development of delayed type hypersensitivity (DTH) to the tumor. Tuberculin hypersensitivity, however, was depressed during the evolution of DTH to the tumor. Antitumor immunity was transferred locally with spleen or lymph node cells that were sensitive to anti-theta sera and complement but not to anti-lg and complement. They had velocity sedimentation rates in a bovine serum albumin gradient of 3.9-5.9 mm/hour and were relatively resistant to vinblastine at the peak of the immune response. Sera from immunized mice failed to confer antitumor immunity either in vitro or on transfer in vivo.

Animals↗
PubMed1999

The search for a vaccine against schistosomiasis--a difficult path but an achievable goal.

The search for an effective vaccine against schistosomiasis, a parasitic disease currently affecting over 200 million people, remains a desirable but as yet challenging and elusive goal. Progress in the area has been relatively slow but research demonstrating the ability of humans to acquire natural immunity to schistosome infection, together with the successful use in animals of attenuated vaccines, supplemented with encouraging results obtained with defined antigens, suggests that development of a vaccine is achievable. Noteworthy also are recent immune correlate findings which shed light on the complex, putatively protective immune responses in humans, which have improved the prospects of success. With the first human clinical trial having been completed with a schistosome vaccine candidate, this review examines current progress aimed at achieving the objective of a safe and effective vaccine for widespread use against schistosomiasis. The review emphasises work undertaken in the author's laboratory and those of his chief collaborators in the search for a vaccine against schistosomiasis japonica, a disease of major public health significance in The People's Republic of China and The Philippines. Schistosomiasis vaccines should not be considered as the panacea for schistosomiasis control as, when available, it is generally envisaged that they would be used as one component of an integrated strategy complementing currently available and effective tools such as chemotherapy, improvements to sanitation, piped water supply, effective sewage draining and health education.

Animals↗
PubMed2005

Comparison of antibody repertoires against Staphylococcus aureus in healthy individuals and in acutely infected patients.

The management of staphylococcal diseases is increasingly difficult with present medical approaches. Preventive and therapeutic vaccination is considered to be a promising alternative; however, little is known about immune correlates of protection and disease susceptibility. To better understand the immune recognition of Staphylococcus aureus by the human host, we studied the antistaphylococcal humoral responses in healthy people in comparison to those of patients with invasive diseases. In a series of enzyme-linked immunosorbent assay analyses performed using 19 recombinant staphylococcal cell surface and secreted proteins, we measured a wide range of antibody levels, finding a pronounced heterogeneity among individuals in both donor groups. The analysis revealed marked differences in the antibody repertoires of healthy individuals with or without S. aureus carriage, as well as in those of patients in the acute phase of infection. Most importantly, we identified antigenic proteins for which specific antibodies were missing or underrepresented in infected patients. In contrast to the well-described transient nature of disease-induced antistaphylococcal immune response, it was demonstrated that high-titer antistaphylococcal antibodies are stable for years in healthy individuals. In addition, we provide evidence obtained on the basis of opsonophagocytic and neutralizing activity in vitro assays that circulating antistaphylococcal serum antibodies in healthy donors are functional. In light of these data we suggest that proper serological analysis comparing the preexisting antibody repertoires of hospitalized patients with different outcomes for nosocomial staphylococcal infections could be extremely useful for the evaluation of candidate vaccine antigens in addition to protection data generated with animal models.

Acute Disease↗