However, protection from progression to AIDS was achieved ( 19, 20). We have shown that rectal immunizations in rhesus macaques (RM) with SIV DNA/recombinant modified vaccinia virus Ankara (rMVA) vaccine were effective in eliciting virus-specific cellular immune responses systemically and mucosally and also anti-SIV IgA antibodies in rectal secretions, but these humoral responses were sporadic and declined quickly over time.
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Thus far, only one vaccine tested in clinical trails and administered intramuscularly has achieved partial protection (31.2% efficacy), the RV-144 ALVAC-HIV (v CP1521) plus AIDSVAX ( 18), supporting the feasibility of achieving protection but also requiring further improvement. In the case of the HIV vaccine, most of the research emphasis is devoted to exploring the intramuscular route of immunization. Different routes for the delivery of mucosal vaccines are being explored these routes include nasal aerosol, intravaginal, rectal, and sublingual routes ( 17). Other examples of vaccines currently in use that are given via the mucosal route are the live-attenuated mucosal vaccines against influenza virus (FluMist), rotavirus, and Salmonella enterica and nonliving whole-cell oral vaccines against Vibrio cholerae and Shigella flexneri ( 10– 16). The OPV is still used in countries with a high prevalence of polio ( 8, 9). The extremely low prevalence of polio in the United States and some risk associated with the use of OPV led to discontinuing it, and since 2000, the IPV has been used in the United States.
One of the most successful mucosal vaccines has been the polio vaccine, and the live attenuated oral polio vaccine (OPV) is more effective than the inactivated polio vaccine (IPV), which is given intramuscularly (i.m.). In humans, only a few vaccines are administered via the oral and intranasal route ( 7). In order to control both entry and systemic dissemination, an effective HIV may need to stimulate both arms of the adaptive immune system, eliciting cellular and humoral immunity systemically as well as at mucosal surfaces. Systemic dissemination usually occurs within a few days, and at that point, the intestinal mucosa is also a site of major virus replication and CD4 + T-cell depletion in addition to lymphoid organs ( 1– 6). Natural transmission of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) occurs predominantly via mucosal surfaces. Of the immunization routes tested, oral vaccination provided the most diverse and significant response to the vaccine. The majority of SIV-specific T cells that produced granzyme B did not produce cytokines. Significantly higher CD8 + granzyme B-positive T-cell responses were observed systemically after intestinal vaccination and in rectal cells after oral immunization. The most balanced, diverse, and higher-magnitude vaginal T-cell responses were observed after intestinal vaccination. Rectal T-cell responses were significantly greater in the orally vaccinated animals than in the other animals. Vaccination also induced CD4 + and CD8 + T-cell responses in the rectal and vaginal mucosa with greater functional heterogeneity than in blood samples. Limited levels of SIV-specific IgG antibodies were detected in plasma samples, and no SIV-specific IgG antibodies were detected in secretions. SIV-specific T cells producing gamma interferon (IFN-γ) dominated these responses. All four immunizations stimulated systemic T-cell responses against Gag and Env, albeit to a different extent, with oral immunization providing greater magnitude and nasal immunization providing wider functional heterogeneity.
Oral immunization was as effective as vaginal immunization in inducing SIV-specific IgA in vaginal secretions and generated greater IgA responses in rectal secretions and saliva samples compared to the other immunization routes. All four immunizations generated mucosal SIV-specific IgA. A comparative evaluation of the immunity stimulated with a vaccine regimen that includes simian immunodeficiency virus (SIV), interleukin 2 (IL-2), and IL-15 DNAs, recombinant modified vaccinia virus Ankara (rMVA), and inactivated SIVmac239 particles administered into the oral and nasal cavities, small intestine, and vagina was carried out in female rhesus macaques to determine the best route to induce diverse anti-SIV immunity that may be critical to protection from SIV infection and disease.
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