Work

Reduced neutralizing antibody production against Omicron XBB.1.5 in people living with HIV

Year: 2024

Type: article

Abstract: To the Editor: The emergence of Omicron has gained global attention since November 2021. Of the Omicron strains, Omicron XBB.1.5 is the most recently identified. It carries deletions and more than 30 mutations, which have modified the biological features of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) for enhanced transmissibility and immune escape capacity.[1] People living with human immunodeficiency virus (PLWH) are featured with acquired cluster of differentiation (CD)4+ T cell deficiency and at a higher risk of progression to severe coronavirus disease 2019 (COVID-19).[2] Vaccines are the most protective tools against SARS-CoV-2 infection.[3] Nevertheless, the extent to which booster vaccination induces neutralizing antibody (NAb) production against Omicron XBB.1.5 in PLWH is not well defined. To investigate the immunogenicity of Omicron XBB.1.5, we recruited 19 PLWH and 23 healthy participants from Beijing Youan Hospital, all of whom received sequential three CoronaVac (Sinovac inactivated vaccine, Beijing, China) injections.[4] The Institutional Review Board of Capital Medical University approved the study (No. 2021-087). All participants gave written informed consent before participating in the study. The first vaccination was conducted between July 2020 and June 2021. The interval between the first and second dose of CoronaVac (Sinovac) was 14 days. Approximately six months after the first dose, they were administered the third dose of CoronaVac (Sinovac). The PLWH were all males with a mean age of 38.3 ± 7.7 years. The healthy subjects had a mean age of 27.5 ± 8.7 years and seven (30.4%) were males. The average absolute CD4+ T cell number in PLWH was 500.3 (95% confidence interval [CI], 382.5–618.1). Of the 19 PLWH, human immunodeficiency virus (HIV) RNA was detected in two individuals (10.5%). Serum samples were obtained before the third CoronaVac injection as a baseline. Afterward, the participants were revisited at day 14 and day 84 post vaccination to collect serum samples. We constructed pseudovirus strains of the SARS-CoV-2 prototype and Omicron XBB.1.5 and quantified the titers of NAb for the different SARS-CoV-2 pseudovirus strains. As assessed by the t-test, the Geometric mean titers (GMT) were similar for both strains at all timepoints regardless of gender (P ≥0.11 for all). At baseline (D0), the NAb GMTs for the prototype and Omicron XBB.1.5 strains were low, but comparable between HC and PLWH, respectively (P = 0.37 for prototype; P = 0.46 for Omicron XBB.1.5)[Figure 1A, B].Figure 1: Immune response induced by the third CoronaVac injection. (A–B) Neutralizing antibody. (C–D) CyTOF analysis of peripheral blood mononuclear cells. Cluster 1, CD8+ T cells; cluster 2, memory CD8+ T cells; cluster 3, naïve CD4+ T cells; cluster 4, memory CD4+ T cells; cluster 5, CD57+ CD8+ T cells; cluster 6, CD57+ NK cells; cluster 7, CD183dimCD45– cells; cluster 8, NK cells; cluster 9, B cells; cluster 10, monocytes; cluster 11, CD183+CD196+ monocytes; and cluster 12, follicular B cells. (E) Circulating cytokine levels at day 14 after the 3rd administration. (F–G) Correlation matrix. * P <0.05; † P <0.01; ‡ P <0.001. CyTOF: Mass cytometry; ED50: Median effective dose 50; HC: Healthy control; IL: Interleukin; IP-10: Interferon-γ-inducible protein 10; NK: Nature killer; M-CSF: Macrophage colony stimulating factor; MIG: Monokine-induced-by IFN-γ; PLWH: People living with human immunodeficiency virus; TNF-α: Tumor necrosis factor-α; t-SNE: T-distributed stochastic neighbor embedding; VEGF-A: Vascular endothelial growth factor-A.Fourteen days after the third vaccination, the prototype NAb GMTs increased by 15.4-fold and 12.6-fold for healthy control (HC) and PLWH, respectively, over their corresponding baseline levels (HC: 765.3 [95% CI, 518.6–1012.0] vs. 49.6 [95% CI, 36.3–62.9], P <0.0001; PLWH: 554.5 [95% CI, 298.6–810.4) vs. 44.1 [95% CI, 33.0–55.3, P <0.0001]). The GMTs for the prototype did not differ between HC and PLWH at day 14 and day 84 after vaccination, respectively (day 14: P = 0.10; day 84: P = 0.14) [Figure 1A]. Nevertheless, the GMT for Omicron XBB.1.5 had increased by 3.8-fold and by 1.6-fold in the HC and in PLWH, respectively, compared with their baseline values (HC: 66.5 [95% CI, 44.4–88.6] vs. 17.7 [12.1–23.3], P <0.0001; PLWH: 38.9 [95% CI, 22.4–55.4] vs. 24.9 [95% CI, 14.6–35.2], P = 0.043) [Figure 1A, B]. At day 84, the GMTs for the prototype had decreased to 570.0 and 469.8 for HC and PLWH, respectively (P = 0.76). Likewise, the GMTs for Omicron XBB.1.5 declined to 25.5 and 30.4 for HC and PLWH, respectively (P = 0.73) [Figure 1A, B]. When compared with those at day 14, the GMTs for the prototype and Omicron XBB.1.5 were both 0.8 fold at day 84 in PLWH (P ≥0.92 for both). To dissect how the GMTs for Omicron XBB.1.5 differed between PLWH and HC at day 14 after the third CoronaVac administration, we performed Mass cytometry (CyTOF) on the PBMC samples obtained at the same time. Based on the protein-expression profiles, 12 clusters were categorized as follows: cluster 1, CD8+ T cells; cluster 2, memory CD8+ T cells; cluster 3, naïve CD4+ T cells; cluster 4, memory CD4+ T cells; cluster 5, CD57+ CD8+ T cells; cluster 6, CD57+ nature killer (NK) cells; cluster 7, CD183dimCD45– cells; cluster 8, NK cells; cluster 9, B cells; cluster 10, monocytes; cluster 11, CD183+ CD196+ monocytes; and cluster 12, follicular B cells [Figure 1C]. By t-test analyses, we detected a lower proportion of naïve CD4+ T cells (cluster 3) and memory CD4+ T cells (cluster 4) in PLWH compared with HC (naïve CD4+ T cells: 12.2 ± 5.0% vs. 6.4 ± 4.7%, P = 0.007; memory CD4+ T cells: 13.2 ± 5.2% vs. 8.6 ± 3.6%, P = 0.026). In contrast to the lower proportion of CD4+ T cells, CD183dimCD45– cells (cluster 7) were 1.8-fold higher in PLWH than in HC (9.8 ± 4.4% vs. 18.0 ± 7.2%, P = 0.004) [Figure 1D]. We further quantified the expression of a panel of cytokines and chemokines in the plasma samples collected at day 14 after the third vaccination. PLWH had higher plasma levels of the interleukin-1 receptor antagonist (IL-1RA), IL-6, IL-12 (p40), IL-27, interferon-γ-inducible protein 10 (IP-10), macrophage colony stimulating factor (M-CSF), monokine-induced-by IFN-γ (MIG), tumor necrosis factor (TNF)-α, and vascular endothelial growth factor (VEGF)-A, ranging between 1.5-fold and 3.4-fold, compared with HC [Figure 1E]. Among these cytokines, the Pearson analysis revealed that IP-10 levels were strongly, positively related to IL-6, IL12 (p40), MIG, and TNF-α levels (P <0.001 for all) [Figure 1F, G]. Similarly, a positive correlation was also noticed between IL-6 and IL-12 (p40), IP-10, MIG, and TNF-α in the circulation. Paradoxically, IL-1RA levels were not significantly related to any other cytokine level (P ≥0.10 for all). A correlation co-efficient was determined for each interaction [Figure 1F, G]. Finally, we investigated how the NAb levels at day 14 after the third vaccination were related to the identified cytokines and chemokines. In response to RNA vaccines, IL-1RA was induced to inhibit IL-1β-mediated inflammation. By doing so, IL-1RA regulated the adaptive immune response to RNA vaccines.[5] Consistent with this finding, by univariate linear regression analysis, the plasma levels of IL-1RA were positively associated with the fold change in the levels of NAb against the prototype strain between day 0 and day 14 following the third vaccination (r = 0.40, P = 0.03). By contrast, circulating IL-1RA levels were not related to the fold induction of NAb against Omicron XBB.1.5 before or after the third vaccination (r = 0.004, P = 0.98). After adjusting for age and sex, the positive association between plasma IL-1RA levels and the fold induction of NAb against the prototype strain was retained (P = 0.009). However, IL-1RA levels were not significantly related to NAb for Omicron XBB.1.5. Taken together, these data suggest that the immune machinery induced by CoronaVac for the prototype strain is not sufficient to promote comparable NAb induction against Omicron XBB.1.5. As such, a specific vaccine against Omicron XBB.1.5 is needed to generate more potent immune protection. Aside from IL-1RA, the other cytokines were not related to the fold induction of NAb against the prototype or Omicron XBB.1.5 strains (P ≥0.07 for all) [Figure 1F, G]. When adjusting for confounding factors, no significant association was found (P ≥0.44 for all). The study must be interpreted in the context of its limitations. First, we focused on NAb levels following the booster CoronaVac injection. The effect of the booster vaccination on neutralization and real-world vaccine effectiveness against Omicron XBB.1.5 should be evaluated. Second, the sample size is relatively small, and the findings of the study await further confirmation. Third, a higher number of CD183dimCD45– cells was seen in vaccinated PLWH compared with HC. Based on its surface marker expression, this cluster did not comprise blood cells. The origin and function of this cluster in the setting of infection and vaccination remain to be uncovered. In conclusion, the CoronaVac booster administration triggered the dramatic elevation of GMTs against the prototype virus in both PLWH and healthy participants. NAb against Omicron XBB.1.5 were also induced, but to a lesser extent in PLWH than in healthy subjects. Circulating IL-1RA levels positively associated with NAb against the prototype strain, but not against Omicron XBB.1.5, indicating that the inactivated vaccine only weakly activated the immune system against the Omicron strain. Funding This work was supported by a grant from the National Key R&D Program of China (No. 2023YFC0872400).

Source: Chinese Medical Journal

DOI: 10.1097/cm9.0000000000003139