Immunological Correlates Of Protection Research Articles

Immunologic correlates of protection against rotavirus challenge after intramuscular immunization of mice.

The capacity of intramuscular (i.m.) inoculation of mice with homologous or heterologous host rotaviruses to induce protection from challenge was evaluated. i.m. inoculation with live, wild-type rotavirus (murine strain EDIM) induced complete protection from viral shedding after challenge for at least 6 weeks after inoculation; protection was correlated with production of virus-specific immunoglobulin A (IgA) by lamina propria (LP) lymphocytes. i.m. inoculation with inactivated EDIM, cell culture-adapted EDIM, or simian strain RRV was associated with partial protection, characterized by reduced viral shedding after challenge. Partial protection after challenge was not associated with production of virus-specific IgA by LP lymphocytes. The mechanisms by which i.m. inoculation induces virus-specific humoral immune responses in the small intestinal LP were examined.

Cross-protective immune responses induced in rhesus macaques by immunization with attenuated macrophage-tropic simian immunodeficiency virus.

The simian immunodeficiency virus (SIV) macaque model of AIDS has provided a valuable system with which to investigate vaccine approaches for protection against human immunodeficiency virus type 1 (HIV-1) infection. In particular, the ability of macaques persistently infected with attenuated infectious molecular clones of SIV to resist challenge with the pathogenic parental swarm has conclusively demonstrated that protective immunity can be achieved by immunization prior to exposure. The breadth of these protective responses and the immunological correlates of protection, however, have not been identified. In addition, vaccine studies have mainly employed lymphocyte-tropic strains of HIV-1 and SIV. Recent studies have implicated macrophage-tropic strains in the transmission of HIV-1 and have suggested that these virus strains should be examined in vaccine strategies. Macrophage-tropic viruses may confer additional advantages in the induction of protective immunity by replication in antigen-presenting cells. In this study, the immune response of rhesus macaques inoculated with an attenuated macrophage-tropic recombinant of SIVmac239 (SIV/17E-Cl) was evaluated with respect to protective immunity by heterologous challenge at various times after infection. Vigorous type-specific neutralizing-antibody responses restricted to SIV/17E-Cl were evident by 2 weeks postinfection. By 7 months, however, cross-reactive neutralizing antibodies emerged which neutralized not only SIV/17E-Cl but also the heterologous primary isolate SIV/DeltaB670. Challenge of SIV/17E-Cl-infected monkeys with SIV/DeltaB670 at various times postinfection demonstrated that protective responses were associated with the appearance of cross-reactive neutralizing antibodies. Furthermore, passive transfer of sera from SIV/17E-Cl-infected animals passively protected two of four naive recipients.

The development and evaluation of HIV vaccines

Experimental simian immunodeficiency virus and human immunodeficiency virus (HIV) vaccines have been shown to induce protective immunity in macaques and chimpanzees, respectively. Immunologic correlates of protection have not been established, although in the case of HIV vaccines, gp120-, V3-specific neutralizing antibodies may be involved. V3 sequences are strain specific, and the genetic and antigenic variability of HIV may present an obstacle for vaccine development. However, in addition to anti-V3 antibodies, the immune response to HIV infection (and immunization) involves group-specific neutralizing antibodies directed against conformational epitopes in the gpl20-CD4 binding site, as well as an array of cell-mediated immune responses against several HIV proteins. Safety and immunogenicity human trials (Phase l/ll) of 12 candidate vaccines tested in HIV-negative volunteers have shown that, in general, they are well tolerated and induce neutralizing antibodies and different cell-mediated responses. Safety and immunogenicity trials of four candidate vaccines in HIV-infected volunteers have shown that they are safe and capable of increasing anti-HIV immune responses, although no information has been obtained on potential clinical benefits. Criteria for initiating efficacy (Phase III) trials of preventive candidate vaccines are being discussed by the scientific community, and appropriate study populations are being identified and prepared by industrialized and developing countries through collaboration with the World Health Organization and other national and international HIV vaccine research programs.