Highly Attenuated Vaccine Strains of Simian Immunodeficiency Virus Protect against Vaginal Challenge: Inverse Relationship of Degree of Protection with Level of Attenuation

Abstract

Three different deletion mutants of simian immunodeficiency virus (SIV) that vary in their levels of attenuation were tested for the ability to protect against mucosal challenge with pathogenic SIV. Four female rhesus monkeys were vaccinated by intravenous inoculation with SIVmac239Δ3, four with SIVmac239Δ3X, and four with SIVmac239Δ4. These three vaccine strains exhibit increasing levels of attenuation: Δ3 < Δ3X <Δ4. The vaccinated monkeys were challenged by vaginal exposure to uncloned, pathogenic SIVmac251 at 61 weeks after the time of vaccination. On the basis of viral RNA loads in plasma, cell-associated virus loads in peripheral blood, and CD4 cell counts, strong protective effects were observed in all three groups of vaccinated monkeys. However, the degree of protection correlated inversely with the level of attenuation; the least-attenuated strain, SIVmac239Δ3, gave the greatest protection. One monkey in the Δ3X group and two in the Δ4 group clearly became superinfected by the challenge virus, but these animals had levels of SIV RNA in plasma that were considerably lower than those of naive animals that were challenged in parallel. Protection against vaginal challenge appears easier to achieve than protection against intravenous challenge, since four other SIVmac239Δ4-vaccinated monkeys showed no protection when challenged intravenously with a much lower inoculum of the same challenge virus stock. Protection against vaginal challenge in the Δ4-vaccinated group occurred in the absence of detectable serum neutralizing activities and appeared to be associated with the development of an early SIV-specific cytotoxic-T-lymphocyte response. Our results demonstrate that mucosal protection can be achieved by systemic immunization with the highly attenuated SIVmac239Δ4 more than 1 year prior to the time of challenge.

The mucosal humoral immune response of the horse to infective challenge and vaccination with Equine herpesvirus‐1 antigens

“…Rhinomune failed to induce mucosal antibodies in any individual despite experimental intranasal delivery. P r e s u m a b l y, attenuation had rendered it a poor mucosal immunogen (Johnson et al 1999). As expected, intramuscular delivery of Pneumabort K similarly failed to induce mucosal antibodies.…”

Protection by Live, Attenuated Simian Immunodeficiency Virus against Heterologous Challenge

“…The results described in this report and in another recent manuscript from our group (18) focus attention on the potential of cellular responses, particularly CTL, to Gag and Pol for controlling SIV and SHIV infection. In the recent study (18), monkeys were vaccinated with SIVmac239⌬3X and SIVmac239⌬4 and were challenged vaginally.…”

“…Infection by live, attenuated deletion mutants of simian immunodeficiency virus (SIV) has afforded rhesus monkeys strong protection against subsequent challenge by wild-type, disease-causing strains of SIV (4,7,18,36). While it has been argued that this protection could result from some sort of blocking or interference phenomenon (13,32,34), several lines of circumstantial evidence suggest that the protection may be immune mediated (16).…”

“…Protection has been shown to be time dependent: the longer the time interval, the better the protection, despite the fact that vaccine virus loads are highest during the initial weeks following immunization (4,36). While the most solid protection has been observed in monkeys with apparent sterilizing immunity, some animals have exhibited longterm protective effects despite a transient take of the challenge virus (18,36), again apparently more consistent with immunemediated protection than with viral interference. Monkeys that control replication of SIVmac239⌬nef least effectively are the least protected upon subsequent challenge (23).…”

Wie impft man Fohlen richtig?

“…Auch die intranasale Erstimpfung mit Lebendimpfstoff, gefolgt von einer Zweitimpfung mit inaktiviertem Antigen, wurde bezüglich der Postchallenge-Schleimhautimmunität deutlich schlechter beantwortet als die Impfungen unter Einsatz von Impfstoff mit inaktiviertem EHV1. Die Autoren diskutieren, dass die Attenuierung des vorliegenden EHV1-Stammes im Lebendimpfstoff dessen Immunogenität signifikant reduziert habe (18,51).…”