Administration of a Toll-Like Receptor 9 Agonist Decreases the Proviral Reservoir in Virologically Suppressed HIV-Infected Patients

<div><p></p><p>Toll-like receptor (TLR) agonists can reactivate HIV from latently infected cells in vitro. We aimed to investigate the TLR-9 agonist, CPG 7909's <i>in vivo</i> effect on the proviral HIV reservoir and HIV-specific immunity. This was a post-hoc analysis of a double-blind randomized controlled vaccine trial. HIV-infected adults were randomized 1∶1 to receive pneumococcal vaccines with or without 1 mg CPG 7909 as adjuvant at 0, 3 and 9 months. In patients on suppressive antiretroviral therapy we quantified proviral DNA at 0, 3, 4, 9, and 10 months (31 subjects in the CPG group and 37 in the placebo-adjuvant group). Furthermore, we measured HIV-specific antibodies, characterized T cell phenotypes and HIV-specific T cell immunity. We observed a mean reduction in proviral DNA in the CPG group of 12.6% (95% CI: −23.6–0.0) following each immunization whereas proviral DNA in the placebo-adjuvant group remained largely unchanged (6.7% increase; 95% CI: −4.2–19.0 after each immunization, p = 0.02). Among participants with additional cryo-preserved PBMCs, HIV-specific CD8+ T cell immunity as indicated by increased expression of degranulation marker CD107a and macrophage inflammatory protein 1β (MIP1β) tended to be up-regulated following immunization with CPG 7909 compared with placebo as adjuvant. Further, increasing proportion of HIV-specific CD107a and MIP1β-expressing CD8+ T cells were strongly correlated with decreasing proviral load. No changes were observed in T cell phenotype distribution, HIV-specific CD4+ T cell immunity, or HIV-specific antibodies. TLR9-adjuvanted pneumococcal vaccination decreased proviral load. Reductions in proviral load correlated with increasing levels of HIV specific CD8+ T cells. Further investigation into the potential effect of TLR9 agonists on HIV latency is warranted.</p></div

Disposition of study participants.

<p>HAART, highly active antiretroviral therapy.</p

Proviral load.

<p>Relative changes in proviral load before and after immunization. <b>(A)</b> Before and 3 months after the 1^st immunization. N = 43 (placebo = 22, CPG = 21) <b>(B)</b> Before and 1 month after the 2^nd immunization. N = 47 (placebo = 24, CPG = 23) <b>(C)</b> Before and 1 month after the 3^rd immunization. N = 43 (placebo = 21, CPG = 22) <b>(D)</b> Pooled data from before and after all three immunizations. N = 133 (placebo = 67, CPG = 66). Bars show mean with SEM.</p

Baseline Characteristics of the Study Population at Time of Inclusion in the Study.

<p>Note: Data are no. (%) of patients, unless otherwise is indicated. BMI, body mass index; PBMCs, IQR, interquartile range.</p

HIV-specific T cell immunity.

<p>Percentage of cells expressing CD107a, MIP1β and IFNγ before and after the 3^rd immunization in the <b>(A)</b> CD4+ T cell compartment and <b>(B)</b> CD8+ T cell compartment. Bars show mean with SEM. N = 17 (placebo = 10, CPG = 7). Statistical comparisons were made between the change from before and after the 3^rd immunization in the two groups.</p

HIV-specific antibodies.

<p><b>(A)</b> Quantitative antibodies <b>(B)</b> Neutralizing antibodies.</p

T-cell phenotype at baseline and the end of the study in (A) the CD4+ T cell and (B) CD8+ T cell compartment.

<p>T-cell phenotype at baseline and the end of the study in (A) the CD4+ T cell and (B) CD8+ T cell compartment.</p

Analysis of Neutralization Titers against SARS-CoV-2 in Health-Care Workers Vaccinated with Prime-Boost mRNA–mRNA or Vector–mRNA COVID-19 Vaccines

With increasing numbers of vaccine-breakthrough infections worldwide, assessing the immunogenicity of vaccinated health-care workers that are frequently exposed to SARS-CoV-2-infected individuals is important. In this study, neutralization titers against SARS-CoV-2 were assessed one month after completed prime-boost vaccine regimens in health-care workers vaccinated with either mRNA–mRNA (Comirnaty(®), BioNTech-Pfzier, Mainz, Germany/New York, NY, USA, n = 98) or vector-based (Vaxzevria(®), Oxford-AstraZeneca, Cambridge, UK) followed by mRNA-based (Comirnaty(®) or Spikevax(®), Moderna, Cambridge, MA, USA) vaccines (n = 16). Vaccine-induced neutralization titers were compared to time-matched, unvaccinated individuals that were infected with SARS-CoV-2 and presented with mild symptoms (n = 38). Significantly higher neutralizing titers were found in both the mRNA–mRNA (ID(50): 2525, IQR: 1667–4313) and vector–mRNA (ID(50): 4978, IQR: 3364–7508) prime-boost vaccine regimens when compared to SARS-CoV-2 infection (ID(50): 401, IQR: 271–792) (p < 0.0001). However, infection with SARS-CoV-2 induced higher titers when compared to a single dose of Vaxzevria(®) (p = 0.0072). Between mRNA–mRNA and vector–mRNA prime-boost regimens, the vector–mRNA vaccine regimen induced higher neutralization titers (p = 0.0054). Demographically, both age and time between vaccination doses were associated with vaccine-induced neutralization titers (p = 0.02 and p = 0.03, respectively). This warrants further investigation into the optimal time to administer booster vaccination for optimized induction of neutralizing responses. Although anecdotal (n = 3), those with exposure to SARS-CoV-2, either before or after vaccination, demonstrated superior neutralizing titers, which is suggestive of further boosting through viral exposure