Risk of Immunodeficiency Virus Infection May Increase with Vaccine-Induced Immune Response

Abstract

e To explore the efficacy of novel complementary prime-boost immunization regimens in a nonhuman primate model for HIV infection, rhesus monkeys primed by different DNA vaccines were boosted with virus-like particles (VLP) and then challenged by repeated low-dose rectal exposure to simian immunodeficiency virus (SIV). Characteristic of the cellular immune response after the VLP booster immunization were high numbers of SIV-specific, gamma interferon-secreting cells after stimulation with inactivated SIV particles, but not SIV peptides, and the absence of detectable levels of CD8 ؉ T cell responses. Antibodies specific to SIV Gag and SIV Env could be induced in all animals, but, consistent with a poor neutralizing activity at the time of challenge, vaccinated monkeys were not protected from acquisition of infection and did not control viremia. Surprisingly, vaccinees with high numbers of SIV-specific, gamma interferon-secreting cells were infected fastest during the repeated low-dose exposures and the numbers of these immune cells in vaccinated macaques correlated with susceptibility to infection. Thus, in the absence of protective antibodies or cytotoxic T cell responses, vaccine-induced immune responses may increase the susceptibility to acquisition of immunodeficiency virus infection. The results are consistent with the hypothesis that virus-specific T helper cells mediate this detrimental effect and contribute to the inefficacy of past HIV vaccination attempts (e.g., STEP study). Immune escape mechanisms and the diversity of the circulating HIV strains pose many hurdles for the development of an effective HIV vaccine. In addition, testing the efficacy of HIV vaccines in clinical studies is time-consuming and costly. Therefore, only three vaccine strategies have been tested for efficacy in human volunteers so far. A recombinant protein vaccine based on the gp120 surface protein (AIDSVAX) did not provide protection (5, 13), although antibodies to the vaccine antigen were induced. The lack of efficacy was attributed to the absence of neutralizing antibodies. To explore the efficacy of cellular immune responses, volunteers were also immunized with adenoviral vectors carrying gag, pol, and nef of HIV. However, this did not provide protection either, and in a subgroup of volunteers with preexisting antibodies to the adenoviral vector the susceptibility to acquisition of HIV infection was increased (2). The third vaccine strategy tested for efficacy in human volunteers aimed at the induction of cellular and humoral immune responses by combining an avipox vector carrying gag, protease, and env with the AIDSVAX vaccine. The acquisition of HIV infection was reduced by approximately 30% (15), providing the first evidence that protection from HIV infection by vaccination may be possible.Since such an efficacy is probably too low for general use, we explored the efficacy of a novel complementary prime-boost immunization in nonhuman primates. In our previous study, we compared the immunogenicities of dendritic cell (DC)-ta...

Antibody persistence and T-cell balance: Two key factors confronting HIV vaccine development

“…On one hand, they are intimately associated with protection through the provision of T-cell help for antibody production (34) and possibly direct cytolytic activity (9,25,(107)(108)(109). On the other hand, as predicted by Staprans et al (46) and confirmed elsewhere (97,98) in nonhuman primate studies, they can attenuate protection and lead to increased acquisition. The problem is now in focus, but its solution is intimately connected with the solution of antibody persistence.…”

“…However, post hoc studies in nonhuman primates designed to model preexisting Ad5 immunity recapitulated the Step and Phambili trial results (97). Thus, nonhuman primate studies clearly show the possibility that vaccination can increase infection (46,97,98). The fact that the signal was missed in the nonhuman primate studies supporting the Step and Phambili trials (94,95,99) was more indicative of a problem with the study design than with the animal model itself because those studies did not take into account the possibility that preexisting Ad5 immunity could increase infection.…”

Enhancing the Quality of Antibodies to HIV-1 Envelope by GagPol-Specific Th Cells

“…Again, the similarities in Gag-specific CD4 + T cell responses of mice and human vaccinees suggest that the ISH approach may be applicable to humans, as well. Whether this approach can be extended to Th cells with non-HIV specificities needs to be explored, but the idea to avoid possibly detrimental HIV-1-specific CD4 + T cell responses is appealing (58)(59)(60)(61).…”

Novel Vaccine Regimen Elicits Strong Airway Immune Responses and Control of Respiratory Syncytial Virus in Nonhuman Primates

“…The tonsillar spray immunization with rAdV was carried out as described previously (34). From weeks 32 to 98 all of the group E animals (animals 13916, 13928, 13931, 13932, and 13935) were also immunized with unrelated simian immunodeficiency virus (SIV) an-tigens through DNA and viruslike particle vaccines as reported previously (31,35). Viral challenge.…”

“…Given the striking systemic and mucosal cellular and humoral immune responses induced by the DNA prime-tonsillar booster immunization (group E), we decided to extend the study in order to explore the protective efficacy of this immunization regimen. Due to other research commitments, the animals of group E were first included in an immunogenicity study with unrelated SIV antigens between weeks 60 and 84 (35). At 32 weeks after the last SIV immunization, corresponding to 126 weeks after the first RSV-F DNA immunization and 98 weeks after the last tonsillar booster immunization with the RSV-F adenoviral vector, RSV-F specific antibodies were still detectable in the blood and the BAL fluid (Fig.…”