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Poliovirus vaccination responses in HIV-infected patients: correlation with T4 cell counts.

HIV infection is known to impair both cellular and humoral immunity. The antibody levels to poliovirus were measured in 17 HIV-infected and 3 HIV-seronegative homosexual men before and after vaccination with enhanced inactivated poliovirus vaccine (eIPV). The subjects were tested for neutralizing antibodies to poliovirus types 1, 2, and 3; the number of peripheral blood T4 cells and lymphocyte responses after stimulation with phytohemagglutinin, concanavalin A, and pokeweed mitogen were measured. Before vaccination, all subjects demonstrated neutralizing antibodies to the three types of poliovirus. After eIPV administration, a rise in anti-poliovirus antibody titer was noted in subjects whose T4 cell count was greater than 200/ml, whereas the group with low T4 cell counts failed to respond. The response to eIPV immunization correlated with the number of circulating T4 cells and the mitogen-induced lymphocyte stimulation index.

Adult↗

Correlates of protective immune response in tuberculous pleuritis.

Tuberculous pleuritis (TB) provides a good model to study the correlates of protective immune response at the site of infection. To study the in vivo correlates of immunity, cell subset profile and cytokine assay in plasma (BL) and pleural fluid (PF) of 82 patients were done. Lymphocyte proliferation and cytokine response to mycobacterial antigens were measured in 32 subjects to understand the in vitro correlates. Increase in CD4(+) cells and CD4(+)/CD8(+) ratio with selective concentration of interferon (IFN)-gamma, tumour necrosis factor (TNF)-alpha and interleukin (IL)-12 in PF suggests that the CD4(+) population may be of TH1 type. We observed an accelerated lymphoproliferative response to purified protein derivative (PPD) and heat killed Mycobacterium tuberculosis (MTB) in PF cells of both TB and non-TB (NTB) subjects. Interestingly, in in vitro studies, IL-4 levels together with IFN-gamma were significantly increased in the supernatants of PF mononuclear cells (PFMC) of TB patients and showed a shift in immune response towards TH0/TH2 type. PPD and MTB antigens induced an enhanced proliferation of PFMC and also increased in vitro IL-4 response together with apoptosis, thus eliciting a dual response.

Adolescent↗

Co-administration of plasmid expressing IL-12 with 14-kDa Schistosoma mansoni fatty acid-binding protein cDNA alters immune response profiles and fails to enhance protection induced by Sm14 DNA vaccine alone.

Schistosomiasis is an endemic disease that affects 200 million people worldwide. DNA-based vaccine is a promising strategy to induce protective immunity against schistosomiasis, since both humoral and cellular immune responses are involved in parasite elimination. In this study, we evaluated the ability of Sm14 cDNA alone or in association with a plasmid expressing murine interleukin (IL)-12 to induce protection against challenge infection. Mice were immunized with four doses of the DNA vaccine and the levels of protection were determined by worm burden recovery after challenge infection. Specific antibody production to rSm14 was determined by ELISA, and cytokine production was measured in splenocyte culture supernatants stimulated with rSm14 and in bronchoalveolar lavage of vaccinated mice after challenge infection. DNA immunization with pCI/Sm14 alone induced 40.5% of worm reduction. However, the use of pCI/IL-12 as adjuvant to pCI/Sm14 immunization failed to enhance protection against challenge infection. Protection induced by pCI/Sm14 immunization correlates with specific IgG antibody production against Sm14, Th1 type of immune response with high levels of interferon (IFN)-gamma and low levels of IL-4 in splenocyte culture supernatants and in bronchoalveolar lavage after challenge infection. IL-12 co-administration with pCI/Sm14 induced a significant production of nitric oxide in splenocyte culture supernatants and also lymphocyte suppression, with reduced percentage of T cells producing IFN-gamma and tumor necrosis factor-alpha.

Animals↗

Transcutaneous immunization using colonization factor and heat-labile enterotoxin induces correlates of protective immunity for enterotoxigenic Escherichia coli.

Enterotoxigenic Escherichia coli (ETEC) diarrheal disease is a worldwide problem that may be addressed by transcutaneous delivery of a vaccine. In several human settings, protective immunity has been associated with immune responses to E. coli colonization factors and to the heat-labile toxin that induces the diarrhea. In this set of animal studies, transcutaneous immunization (TCI) using recombinant colonization factor CS6 and cholera toxin (CT) or heat-labile enterotoxin (LT) as the adjuvant induced immunoglobulin G (IgG) and IgA anti-CS6 responses in sera and stools and antibody responses that recognized CS6 antigen in its native configuration. The antitoxin immunity induced by TCI was also shown to protect against enteric toxin challenge. Although immunization with LT via the skin induced mucosal secretory IgA responses to LT, protection could also be achieved by intravenous injection of the immune sera. Finally, a malaria vaccine antigen, merzoite surface protein 1(42) administered with CT as the adjuvant, induced both merzoite surface protein antibodies and T-cell responses while conferring protective antitoxin immunity, suggesting that both antiparasitic activity and antidiarrheal activity can be obtained with a single vaccine formulation. Overall, our results demonstrate that relevant colonization factor and antitoxin immunity can be induced by TCI and suggest that an ETEC traveler's diarrhea vaccine could be delivered by using a patch.

Adjuvants, Immunologic↗

Immune complexes in coccidioidomycosis. Correlation with disease involvement.

Circulating immune complexes were quantitated by Clq-binding assays of serum from 73 patients with active coccidioidomycosis, 5 patients with inactive disease, and 34 healthy subjects. Immune complexes were detected in serums of 8 (44%) of 18 patients with active pulmonary disease only and 22 (40%) of 55 patients with active disseminated disease. Results in none of 5 patients with inactive disease and in only 2 (9%) of 34 healthy subjects were positive by the Clq-binding assay. Immune complex levels did not differ in patients with pulmonary disease versus those with disseminated disease. However, immune complexes did correlate with disease involvement. Of 57 patients with coccidioidomycosis involving a single organ system (pulmonary or extrapulmonary), 19 (33%) had immune complexes compared with 6 (67%) of 9 patients with disease involving 2 organ systems, and 5 (71%) of 7 patients with disease of 3 or more organ systems. Immune complex levels correlated with serum IgG, but did not correlate with serum complement-fixing antibody titers to coccidioidin. Rather, the correlation curve between immune complexes and complement-fixing antibody titers yielded a bell-shaped distribution. This distribution pattern suggests that changes in antibody concentration may have effected the size and lattice of immune complexes, resulting in altered detection and/or clearance from the bloodstream.

Antibodies, Fungal↗

Resolution of induced urinary tract infection: an animal model to assess bladder immunization.

The resolution of an Escherichia coli urinary tract infection in the bladder and kidneys of control and immunized rats was used to assess their resistance to experimentally induced infection. Prior intravesical immunization of rats with formalin killed E. coli 06 resulted in faster resolution of an infection that had been induced with viable E. coli 06 than was observed in nonimmunized controls. The faster resolution of infection after immunization correlates with our previous findings of decreased adherence of bacteria to urothelium of immunized rats and supports the hypothesis that local immune responses in the urinary tract may play a role in resistance to recurrent urinary tract infections.

Animals↗

The effect of bovine colostrum supplementation on salivary IgA in distance runners.

Secretory IgA in saliva (s-IgA) is a potential mucosal immune correlate of upper respiratory tract infection (URTI) status. Nutritional supplements may improve mucosal immunity, and could be beneficial to athletes who are at increased risk of URTI. In this study, 35 distance runners (15 female, 20 male, age 35 to 58 y) consumed a supplement of either bovine colostrum or placebo for 12 wk. Saliva samples were taken prior to training at baseline, monthly during supplementation, and 2 wk post supplementation. Median levels of s-IgA increased by 79% in the colostrum group after 12 wk intervention, and the time-dependent change from baseline value was significant (P = 0.0291). This significance was still apparent after adjusting for training volume and self-reporting of upper respiratory symptoms. This study has demonstrated increased s-IgA levels among a cohort of athletes following colostrum supplementation. While this result is statistically significant, its physiological interpretation must be viewed with caution due to the small numbers in this study and the large variability in s-IgA levels.

Adult↗

Vaccination-induced autoimmune vitiligo is a consequence of secondary trauma to the skin.

A major concern for cancer vaccines targeting self-tumor antigens is the risk of autoimmune sequelae. Although antitumor immunity correlates with autoimmune disease in some preclinical models, the mechanism(s) linking antitumor immunity and subsequent autoimmune pathology remain(s) to be determined. In the current study, we demonstrated that intradermal (i.d.) immunization with a recombinant adenovirus (Ad) expressing the murine melanoma antigen tyrosinase-related protein 2 (AdmTrp-2) results in a moderate level of tumor protection against the B16F10 murine melanoma without any vitiligo. Similar immunization with an Ad encoding human Trp-2 (AdhTrp-2) resulted in 50-fold greater protective immunity and produced vitiligo in all of the mice, suggesting that the development of autoimmunity may reflect the potency of the vaccine. Interestingly, delivery of AdhTrp-2 by i.m. injection generated protective immunity comparable with that seen in mice that received the vaccine by the i.d. route, but none of the recipients in the i.m. group developed vitiligo. The cellular and humoral responses in the i.m. immunized mice were greater than in the i.d. group; therefore, the lack of vitiligo was not caused by reduced efficacy of the vaccine. These results led us to hypothesize that vaccine-induced vitiligo was associated with local inflammatory responses. Mice immunized i.m. with AdhTrp-2 did develop vitiligo when they subsequently were injected i.d. with either a control Ad vector or complete Freund's adjuvant, suggesting that vitiligo is initiated by some form of trauma within the skin. Our data demonstrated that autoimmune pathology is not an unavoidable outcome of effective cancer vaccines directed against self-tumor antigens.

Adenoviridae↗

Active and passive immunization against HIV type 1 infection in chimpanzees.

Several vaccine strategies have been developed to prevent primary infection with human immunodeficiency virus (HIV), and some of the candidate vaccines have been tested in chimpanzees to determine their safety, efficacy, and to delineate immune correlates of protection. To date, more than 25 vaccines representing active and passive immunization strategies have been evaluated in the chimpanzee model. Efficacy of a given vaccine was based on protection against primary infection with HIV after intravenous or mucosal challenge with cell-free or cell-associated virus. Based on the results from a majority of the studies, neutralizing antibodies appear to play a major role in preventing primary infection with HIV.

Animals↗

Evaluation of antibody parameters as potential correlates of protection or enhancement by experimental vaccines to equine infectious anemia virus.

We previously demonstrated in trials of a variety of experimental vaccines to equine infectious anemia virus (EIAV) a remarkable spectrum of efficacy ranging from sterilizing protection to severe enhancement of virus replication and disease, depending on the immunization strategy used. This range of vaccine efficacy observed in vivo offers a unique opportunity for evaluating potential in vitro immune correlates of protection and enhancement. We describe here a comprehensive analysis and comparison of EIAV envelope-specific antibody responses elicited by attenuated, inactivated whole virus and envelope subunit vaccines to EIAV, and we evaluate the potential of in vitro antibody assays as correlates of protection or enhancement. Thus vaccine-induced serum antibody responses in experimentally immunized ponies at the day of challenge were assayed using a panel of quantitative, qualitative, and functional in vitro assays, including end-point titer of total and isotypic IgG, serum antibody avidity, conformational dependence, and serum neutralization. The results of these studies revealed substantial differences in the EIAV envelope-specific antibody responses elicited by the different vaccines, indicating the importance of envelope glycoprotein antigen presentation in determining the specificity of vaccine immunity. Although no single in vitro parameter provided a statistically significant correlate of protection or enhancement, the use of multiple parameters (titer, avidity index, and conformation ratio) could be used as a reliable correlate of vaccine protection and that the level of vaccine protection was closely associated with the development of mature antibody responses. These studies demonstrate the importance of using multiple antibody assays to evaluate lentiviral vaccine responses and emphasize the need for the development of new in vitro antibody assays that may provide more insight into vaccine protection and enhancement.

Animals↗

ErbB2 immune response in breast cancer patients with soluble receptor ectodomain.

Investigation of ErbB2 immunity in human breast cancer employing recombinant expression sources in immunoblot analysis revealed ErbB2-specific antibodies of the IgG isotype in sera of 14 of 71 cancer patients and 1 of 31 normal donors. Reactivity was confirmed on ErbB2-specific immunoprecipitates. Independent evidence of existing ErbB2 immunity was obtained after in vitro transformation of peripheral blood leukocytes from six positive patients. Furthermore, in vitro immortalization of B-lymphocytes unmasked existent ErbB2 immunity in 1 of 8 patients negative for ErbB2 serum antibodies. Determining shed ErbB2 extracellular domain as an indirect measure of tumor burden in ErbB2-positive malignancy, elevated serum levels were observed in 16 of 71 breast cancer and 1 of 31 normal donor sera. Strikingly, existing ErbB2 immunity correlated significantly with elevated shed ErbB2 ectodomain among the patients analyzed. Incidence of both ErbB2 immunity and elevated ErbB2 extracellular domain increased with a progressed disease stage and was significantly associated with metastatic breast cancer. These observations implicate soluble ErbB2 amounts in vivo in the development of ErbB2 immunity in breast cancer. They further project serum analysis of ErbB2 immunity and soluble ectodomain as potential markers of disease progression in ErbB2-positive malignancy.

3T3 Cells↗

Induction of immunity in the respiratory tract and protection from bovine herpesvirus type 1 infection by different routes of immunization with recombinant adenovirus.

To investigate the capability of different routes of immunization with replication-competent recombinant adenovirus to induce antigen-specific antibody responses, we immunized cotton rats with a human adenovirus type 5 (HAd5) vector expressing the glycoprotein D (gD) of bovine herpesvirus type 1 (BHV-1) (gD-dE3). Different routes of mucosal and systemic immunization (intraduodenal-oral, intraduodenal, intranasal and intradermal) with gD-dE3 stimulated similar levels of gD-specific IgG in the serum of cotton rats. However, intranasal (i.n.) immunization stimulated higher levels of gD-specific IgA in the lung and nasal washes, and higher frequency of gD-specific antibody secreting cells in the lung than did the intradermal immunization. Higher levels of antibody in the respiratory tract following i.n. immunization correlated with better protection of the lungs against i.n. BHV-1 challenge. Intraduodenal-oral immunization induced more gD-specific antibodies in the respiratory tract than intraduodenal immunization alone. Adenovirus dissemination to most organs tested was evident following each route of immunization, which is important to consider when studying the mechanism of induction of immunity by recombinant adenoviruses.

Adenoviruses, Human↗

DNA vaccines for hepatitis C virus.

Hepatitis C virus is an RNA encoded virus of the Flaviviridae family. In most cases, infections develop into a chronic carrier stage that can result in the onset of cirrhosis and hepatocellular carcinoma over a 20- to 30-year period. Because existing therapies are still of limited benefit and expensive, the development of a vaccine represents a priority to prevent further spreading of the infection. Immune correlates of protection remain poorly defined although increasing evidence suggests that both humoral and cellular immune responses are likely to contribute to protection and/or neutralization of the virus. Current DNA-based vaccines, while capable of generating the latter, appear limited in their capacity to induce a strong and long-lasting antibody response.

Animals↗

[Characteristics of immunity in children with lymphoid hyperplastic diathesis].

As many as 100 children aged 3 months to 4 years with lymphaticohypoplastic diathesis (LHD) were examined for clinico-immunologic++ interrelations. The children suffering from manifest LHD demonstrated the reduction of the amount of circulating T lymphocytes and IgA, IgM and IgG subpopulations. At the same time the changes in local immunity correlating with enlargement of the thymus and lymphoid formations in the nasopharynx were identified. The immunity unbalance in LHD was supported by morphologic and immunologic studies of the tissue of the removed hypertrophied tonsils. The specification of the deranged mechanisms of immunity in LHD requires early diagnosis of the illness, screening of the methods for immunocorrection and closer follow-up of the sick children.

Castleman Disease↗

Correlation between eosinophils and protection against reinfection with Schistosoma mansoni and the effect of human immunodeficiency virus type 1 coinfection in humans.

Longitudinal investigations of an adult male population of Kenyan car washers who have heavy and quantifiable occupational exposure to Schistosoma mansoni cercariae revealed that some individuals develop resistance to reinfection while others remain highly susceptible. We sought to characterize immune correlates associated with host protection in this population. Previous studies have demonstrated an association of peripheral eosinophilia with resistance to reinfection with schistosomes. Thus, we investigated the relationship between the percentage of circulating eosinophils and the effect of human immunodeficiency virus type 1 (HIV-1) coinfection on the susceptibility of the car washers to reinfection with schistosomes. Elevated percentages of circulating eosinophils were associated with resistance to reinfection by S. mansoni in HIV-1-seronegative persons. In the HIV-1-seropositive cohort, low CD4+-T-cell counts were associated with a less intense eosinophilia. Moreover, eosinophils from the car washers expressed high levels of FcepsilonRI beta chain, a molecule important in immunoglobulin E (IgE)-mediated immunity. Levels of FcepsilonRI beta chain expression correlated with serum levels of total and antigen-specific IgE for HIV-1-negative car washers, but this was not the case for individuals coinfected with HIV-1. Overall, these data further implicate eosinophils as having a potential role in development of protective immunity against schistosomes and suggest that changes associated with HIV-1 coinfection increase susceptibility to reinfection.

Adolescent↗

Impaired antibody response to pneumococcal vaccine after treatment for Hodgkin's disease.

To determine if a normal antibody response can develop after therapy for Hodgkin's disease, we immunized 53 patients and 10 normal controls with dodecavalent pneumococcal vaccine. Antibody concentrations three weeks after immunization (geometric mean of 11 serotypes) were 1566 ng of protein nitrogen per milliliter in controls, 963 ng per milliliter after subtotal radiation (P less than 0.05 compared to controls), 658 ng per milliliter after chemotherapy (P less than 0.05), 377 ng per milliliter after subtotal radiation plus chemotherapy (P less than 0.01) and 283 ng per milliliter after total nodal radiation plus chemotherapy (P less 0.001). Low levels of antibody before immunization correlated with a poor response (r = +0.73, P less than 0.001). The ability to respond to immunization improved significantly but did not return to normal as long as four years after combined therapy. The antibody response to pneumococcal vaccine is profoundly impaired in patients who have received intensive treatment for Hodgkin's disease: the ability of this vaccine to protect them from overwhelming postsplenectomy infections remains in doubt.

Adolescent↗

Vaccines against intracellular infections requiring cellular immunity.

Vaccines against a variety of infectious diseases represent one of the great triumphs of medicine. The immune correlates of protection induced by most current vaccines seem to be mediated by long-lived humoral immune responses. By contrast, there are no currently available vaccines that are uniformly effective for diseases such as HIV, malaria and tuberculosis, in which the cellular immune response might be crucial in mediating protection. Here we examine the mechanisms by which long-lived cellular immune responses are generated and maintained in vivo. We then discuss current approaches for vaccination against diseases in which cellular immune responses are important for protection.

Animals↗

Biological considerations in the development of a human immunodeficiency virus vaccine.

Over the last 12 years, many human immunodeficiency virus (HIV) vaccine candidates have been tried in humans, with disappointing results. In particular, recombinant envelope proteins have failed to elicit strong cellular immune responses or neutralizing antibody against many wild-type isolates of HIV-1. Attenuated strains of simian immunodeficiency virus (SIV), although capable of protecting against virulent strains of SIV, often retain residual pathogenicity. These difficulties suggest that it will be necessary to address a number of biological questions that underpin the rational development of an AIDS vaccine: (1) Will natural infection with HIV protect against superinfection? (2) Is partial protection induced by an HIV vaccine adequate to prevent AIDS? (3) What are the immune correlates of protection for an AIDS vaccine? (4) Will a monotypic HIV-1 vaccine confer cross-clade immunity? (5) Is mucosal immunity important for an effective AIDS vaccine? (6) Is there a rationale for therapeutic immunization? Ongoing research that is addressing these questions should lead to the formulation of a safe and effective AIDS vaccine.

AIDS Vaccines↗