A three-dose inactivated SARS-CoV-2 vaccine is sufficient to elicit humoral immune responses in people living with HIV-1.

To the Editor: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus that caused the 2019 coronavirus disease (COVID-19) pandemic. Over two years after the initial outbreak, several more infectious variations of the virus continue to pose a grave threat to global public health.[1] Intense, worldwide efforts for vaccine development have led to several candidate vaccines utilizing a variety of platforms; moreover, new vaccines are gradually entering the clinical evaluation stages, including inactivated vaccines, recombinant protein vaccines, and DNA or RNA vaccines. The safety and immunogenicity of several vaccine platforms, such as BNT162b2 and ChAdOx1, in patients diagnosed with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) have been published.[2] Minor side effects have been reported in some people living with HIV-1 (PLWH) who received the SARS-COV-2 mRNA vaccine.[2] Two inactivated SARS-CoV-2 vaccines produced by Chinese companies have been approved for emergency use by the World Health Organization (WHO) (Sinopharm and Sinovac CoronaVac, Beijing, China); however, there is a paucity in the availability of data pertaining to the use of inactivated vaccines in HIV-infected people. Huang et al[3] addressed the safety and immunogenicity of the inactivated vaccine in HIV-infected people with no serious adverse reactions reported.[4] Among HIV-infected people with less than 500 CD4+ T cells/μL, the serum conversion rate, neutralizing antibody (nAb) positive rate, and the nAb activity rate were lower than in patients with levels greater than 500 CD4+ T cells/μL. Furthermore, alterations in HIV-1 viral load were not significantly associated with vaccine-induced CD4+ T cell activation.[5] Another study testing the effect of low CD4+ T cell counts showed that the immunogenicity elicited by BNT162b2 was dramatically lower in PLWH who had less than 250 CD4+ T cells/μL.[6] Although several studies have shown the safety and immunogenicity of COVID-19 vaccines, few studies address COVID-19 vaccines specifically in PLWH with low CD4+ T cell counts. Here, we investigated whether a three-dose inactivated SARS-CoV-2 vaccine elicited an nAb response in PLWH. This study was approved by the Ethics Committee of Guangzhou Eighth People's Hospital, Guangzhou Medical University (No. 202001134). Written informed consent was obtained from all participants. Inclusion criteria were PLWH aged 18 years or older who were vaccinated with the third dose of the inactivated vaccine (CoronaVac or others) and who regularly followed up at the HIV/AIDS outpatient clinic. Adults with no known immunosuppression who were vaccinated with the three-dose inactivated vaccine were included as positive controls. We excluded potential participants with diabetes, hypertension, cancer, cardiovascular diseases, hepatitis, and renal insufficiency disease. The study design is described in Supplementary Figure 1, https://links.lww.com/CM9/B674. All participants had no history of SARS-CoV-2 infection. The characteristics of participants at enrollment are shown in Supplementary Table 1, https://links.lww.com/CM9/B674. Immunogenicity was assessed after the third vaccine dose via measurement of total plasma SARS-CoV-2 immunoglobulin G (IgG) as well as nAb positivity and percentage activity. We investigated whether HIV status and/or CD4+ T cell count were associated with inactivated vaccine immunogenicity. Compared to PLWH who did not receive any vaccine (n = 56), PLWH participants who received the three-dose inactivated vaccine produced higher receptor binding domain (RBD) binding antibody and nAb levels [Figure 1A and Supplementary Figure 2, https://links.lww.com/CM9/B674]. nAb levels were not significantly different between PLWH treated with stable, combination antiretroviral treatment (ART) (n = 77) and healthy controls (HC, n = 30); however, nAb levels were higher in PLWH treated with ART than in PLWH who were not treated with ART (n = 29). Of the 29 PLWH who were not treated with ART, 18 (62%) were nAb positive compared to the 66 (86%) of the 77 PLWH who were being treated with ART and to 28 (93%) of the 30 HC participants [Figure 1B].Figure 1: A three-dose inactivated SARS-CoV-2 vaccine is sufficient to elicit humoral immune responses in PLWH. (A, B) Neutralization efficacy after three doses of inactivated vaccine. (C, D) Anti-SARS-CoV-2 RBD binding immunoglobulin against different strains of SARS-CoV-2 (Delta and Omicron) as determined by enzyme linked immunosorbent assay. (E, F) Neutralization efficacy was associated with CD4+ T cell count in PLWH, regardless of ART status. (G) Correlation between CD4+ T cell count and nAb responses. (H) Participants were stratified into three subgroups according to ratio of CD4+/CD8+ T cells (<0.6, 0.6–1, and >1). Anti-SARS-CoV-2 nAb responses were compared among the three subgroups. (I) Correlation between CD4+/CD8+ T cell ratio and anti-SARS-CoV-2 nAb responses. Each dot represents one individual donor. Unpaired two-tailed t-test: * P <0.01, † P <0.001, ‡ P <0.0001. ART: Antiretroviral treatment; HC: Healthy control; nAb: Neutralizing antibody; ns: Not significant; PLWH: People living with HIV-1; RBD: Receptor binding domain; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2.To determine the extent of rise in the breakthrough infections caused by increased viral resistance to vaccine-induced immunity to the Delta and Omicron variants, we measured the RBD binding ability of plasma anti-variant IgG using enzyme-linked immunosorbent assay (ELISA). The results were similar to those of the nAb, but Omicron binding ability was much lower [Figure 1C,D]. This finding indicated that PLWH who received the three-dose inactivated vaccine could exhibit neutralization of the wild-type virus. To investigate whether HIV CD4+ counts could influence vaccine-induced antibody responses in PLWH, we performed a subgroup analysis. PLWH who were not treated with ART with greater than 200 CD4+ T cells/μL could better elicit an nAb and RBD-IgG response than PLWH treated with ART who had less than 200 CD4+ T cells/μL [Figure 1E and Supplementary Figure 3A, https://links.lww.com/CM9/B674]. Of the PLWH who were not treated with ART, only 1 of the 9 patients with less than 200 CD4+ T cells/μL were nAb positive compared with 17 (85%) of the 20 patients who had greater than 200 CD4+ T cells/μL [Figure 1E]. The results of PLWH who were on ART were similar to PLWH without ART, but the ability of vaccine to induce antibodies was greatly improved in PLWH who were treated with ART [Figure 1F and Supplementary Figure 3B, https://links.lww.com/CM9/B674]. In PLWH treated with ART, 10 (50%) out of 20 participants who had less than 200 CD4+ T cells/μL were nAb positive compared with 28 (85%) out of 33 who had greater than 200 CD4+ T cells/μL; 24 (96%) out of 25 who had greater than 500 CD4+ T cells/μL in PLWH on ART had nAb [Figure 1F]. We analyzed the correlation between CD4 counts and nAb or RBD binding IgG. There was a significantly positive correlation between CD4 counts and nAb or RBD binding IgG [Figure 1G and Supplementary Figure 3C, https://links.lww.com/CM9/B674]. There were no differences between HIV viral load and the generation of RBD-IgG or nAb [Supplementary Figure 4, https://links.lww.com/CM9/B674]. However, ART treatment allowed a more robust response to the inactivated vaccine, resulting in greater RBD-IgG and nAb responses in PLWH, particularly in those with greater than 200 CD4+ T cells/μL [Supplementary Figure 5, https://links.lww.com/CM9/B674]. To further elucidate whether immune status affected the vaccine-induced antibody response in PLWH, we further analyzed the relationship between the patients' CD4+/CD8+ T cell ratio and the antibody response after vaccination. The RBD binding and nAb responses were significantly lower in PLWH with low CD4+/CD8+ T cell ratios (<0.6) as compared to those with medium (0.6–1) or high (>1) CD4+/CD8+ T cell ratios. Moreover, there was a significantly positive correlation between CD4+/CD8+ T cell ratio and nAb or RBD binding IgG [Figure 1H,I and Supplementary Figure 6, https://links.lww.com/CM9/B674]. Furthermore, there was no correlation between RBD-IgG or nAb and time post-immunization (weeks since third dose of vaccine) [Supplementary Figure 7A,B, https://links.lww.com/CM9/B674]. There was also no correlation between patient age and antibody response to vaccination [Supplementary Figure 7C,D, https://links.lww.com/CM9/B674]. Thus, these data indicate that the efficacy of a three-dose inactivated SARS-CoV-2 vaccine was positively correlated with CD4+ T cell count and that the response to immunization is inferior in PLWH with less than 200 CD4+ T cells/μL. This study demonstrates the overall profile and seroconversion patterns of SARS-COV-2 binding IgG and neutralizing antibodies after immunization with a three-dose inactivated SARS-CoV-2 vaccine in serum samples from 236 PLWH. Even if HIV replication is controlled by ART, PLWH still struggle to mount an effective response to infectious diseases. Therefore, the WHO suggests that PLWH whose CD4+ T cell counts exceed 200 CD4+ T cells/μL receive vaccination.[7] However, due to their impaired immune status, vaccine-induced immune response may also be impaired in PLWH. In this study, we provide evidence that an inactivated SARS-CoV-2 vaccine induces an immune response against SARS-COV-2 antigens in PLWH. Funding This work was supported by grants from the Key R&D Program of Guangdong Province (No. 2021A1111110002), the Guangzhou Basic Research Program on People's Livelihood Science and Technology (No. 202002020005), and the National Natural Science Foundation of China (No. 82072265). Conflicts of interest None.