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Safety and Antibody Response to Two-Dose SARS-CoV-2 messenger RNA Vaccination in Persons with HIV
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Download the PDF here
Download the PDF here
Jake A. Ruddy BS1, Brian J. Boyarsky MD1, Justin R. Bailey MD PhD2, Andrew H. Karaba MD PhD2, Jacqueline M. Garonzik-Wang MD PhD1, Dorry L. Segev MD PhD1,3, Christine M. Durand MD2, William A. Werbel MD2
1 Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD.
2 Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
3 Department of Epidemiology, Johns Hopkins School of Public Health, Baltimore, MD.
Summary
This study of SARS-CoV-2 mRNA vaccination in 14 persons with HIV demonstrated uniformly high anti-SARS-CoV-2 receptor binding domain antibody titers after two doses, despite varied titers after a single dose. The majority of vaccine reactions were mild and no adverse events occurred.
Keywords: human immunodeficiency virus, COVID-19, SARS-CoV-2, mRNA vaccination, antibody
Early studies indicate that persons with HIV (PWH) may appear to be at increased risk of severe COVID-19 infection, potentially due to increased rates of multimorbidity.[1-3] While the original SARS-CoV-2 mRNA vaccine trials found near-universal robust immune responses in the general population,[4,5] certain immunocompromised populations appear to mount much lower antibody titers.[6-10] Antibody response to SARS-CoV-2 vaccination in PWH has not been reported, and furthermore, given lower antibody response in PWH to common viral vaccine targets such as hepatitis B, [11] it is important to evaluate SARS-CoV-2 vaccine immunogenicity in PWH. After a single dose of a SARS-CoV-2 mRNA vaccine, we demonstrated that PWH showed detectable, yet variable antibody responses, including low titers among persons with CD4 T cell counts <200 cells/mm3.[12] We thus aimed to study boosted antibody response and safety of the two-dose SARS-CoV-2 mRNA vaccine in PWH.
PWH ≥18 years old were recruited to this prospective observational cohort from 12/7/2020 to 4/25/2021 via social media outreach to national HIV/AIDS organizations. As previously described,[12] self-reported demographics, SARS-CoV-2 infection history, most recent HIV viral load (detectable/undetectable), most recent CD4 count (<200, 200-350, 350-499, or ≥500 cells/mm3), p-resence/absence of current antiretroviral therapy (ART), and duration of ART treatment (<6 months or ≥6 months) were collected using the Research Electronic Data Capture (REDCap) tool, a secure, web-based software platform designed to support data capture for research studies.[13]
Prior to dose 2 (titer 1, T1) and one month after D2 (titer 2, T2), participants underwent SARS-CoV-2 antibody testing on the semi-quantitative Roche Elecsys® anti-SARS-CoV-2 S enzyme immunoassay which measures total antibody (IgM, IgG) to the receptor binding domain (RBD), a critical target of neutralizing antibodies within the spike protein encoded by the mRNA vaccines.[14] Results ranged from <0.4 to >250 U/mL (upper reported assay limit) with a positive response defined by the manufacturer as ≥0.8 U/mL. One week after each dose, participants completed a reactogenicity questionnaire indicating local (pain, swelling, or erythema) and systemic symptoms experienced (fatigue, headache, myalgia, chills, fever, diarrhea, or vomiting) on an ordinal scale (similar to reporting in original vaccine trials [15,16]): none, mild (does not interfere with activity), moderate (some interference with activity), or severe (prevents daily activity). Major adverse events were also assessed (i.e., incident anaphylaxis, neurologic diagnoses, or infections including SARS-CoV-2). This study was approved by the Johns Hopkins Institutional Review Board (IRB00248540) and participants provided informed consented electronically.
We studied 14 PWH who reported receiving two doses (dose 1 [D1] and dose 2 [D2]) of a SARS-CoV-2 mRNA vaccine (Supplemental Table, http://links.lww.com/QAD/C238). The median (IQR) age was 62 (56, 70), 13 (93%) were male, 12 (86%) were white, and none had a pre-vaccination history of COVID-19. At vaccination, all were on ART for ≥6 months and 13 (93%) had an undetectable HIV viral load. Two (14%) had CD4 counts <200 cells/mm3, whereas 1 (7%), 3 (21%), and 8 (57%) had CD4 counts of 200-349, 350-499, ≥500 cells/mm3, respectively.
Five (36%) received the Pfizer/BioNTech BNT162b2 vaccine and 9 (64%) received the Moderna mRNA-1273 vaccine. T1 samples were collected on 10 (71%) participants, whereas all 14 (100%) had T2 samples. Median (IQR) time between D1 and T1 was 21 (16, 27) days, and 29 (28, 32) days between D2 and T2. Median (IQR) T1 was 76 (5, 149) U/mL and all participants had a T2 >250 U/mL apart from 239 U/mL in one participant with a CD4 count <200 cells/mm3 (Figure).
The majority of local and systemic reactions were mild (Supplemental Figure, http://links.lww.com/QAD/C237). Local mild or moderate symptoms were reported by 12 (86%) after D1 and 13 (93%) after D2, most commonly pain (12, 86% after D1 and 13, 93% after D2). Systemic symptoms were reported by 10 (71%) after D1 and 9 (64%) after D2, most commonly fatigue (6, 43% after D1 and 8, 57% after D2). One (7%) participant reported severe headache after D2. All local and systemic reactions were more common after D2 apart from local injection site erythema (Supplemental Figure, http://links.lww.com/QAD/C237). No participant experienced anaphylaxis or developed a new infection or a neurologic condition.
In this study of antibody response to two-dose SARS-CoV-2 mRNA vaccination in PWH with excellent virologic control on ART, all participants developed high titers of anti-RBD antibodies. Reactions were generally mild, increased after D2, and comparable to those seen in both the original trials[15,16] and in other immunocompromised populations.[17,18] While titers after a single dose varied across a range of CD4 counts, all participants had titers near or above the upper reported assay limit after two doses. Although no specific titer has been precisely correlated with protection from COVID-19 after vaccination, plasma antibody titers from 15-133 U/mL using the Roche Elecsys anti-RBD assay have been correlated with neutralizing serum activity in vitro.[19, 20] Additionally, the post-D2 titers observed in this study are comparable to those seen in immunocompetent, HIV-uninfected populations (i.e. median titers >250 U/mL after D2).[21,22] These results contrast with antibody response after SARS-CoV-2 mRNA vaccination in other immunocompromised patients on lymphocyte-modulating agents (e.g., antimetabolites and rituximab), which have been shown to severely impair antibody production.[6-9]
PWH with CD4 counts <200 cells/mm3 have shown diminished SARS-CoV-2 antibody production after acute infection,[23,24] as well as blunted immune responses to multiple vaccine types.[11,25-27] However, although two participants with CD4 counts <200 cells/mm3 demonstrated low T1s (2 and 3 U/mL), both exhibited substantial boosting with a second dose (239 and >250 U/mL).
Limitations of this study include a small, non-randomized sample, relatively homogeneous in sex and race, and representing PWH with excellent virologic control on ART. These initial results show encouraging immunogenicity and safety of the two-dose mRNA vaccine series, suggesting that all PWH with viral suppression, regardless of CD4 count, may benefit from vaccination. Future study should include serial antibody sampling as well as integration of cellular immune responses to further characterize the durability and breadth of immune response to COVID-19 vaccination in PWH.
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The BNT162b2 mRNA Vaccine Elicits Robust Humoral and Cellular Immune Responses in People Living with HIV
Clinical Infectious Diseases 22 July 2021
Introduction
The BNT162b2 mRNA vaccine induces robust and protective humoral and cellular response to the SARS-Cov-2 spike protein (1) and provides protection from infection with SARS-CoV-2 (2). However, prior studies have shown suboptimal responses to some vaccines in people living with HIV (PLWH) (3). A recent study demonstrated that the ChAdOx1 nCoV-19 (AZD1222) vaccine was effective at inducing humoral and cellular immune responses in PLWH (4), but few studies have addressed the immunogenicity of mRNA vaccines in these patients (5, 6). Here, we deter-mined the capacity of the BNT162b2 mRNA vaccine to induce effective cellular and humoral immune responses in PLWH.
Methods
We obtained blood between 7 and 17 days after the second vaccine dose from 12 PLWH (7 women, 5 men) and 17 healthy donors (7 women, 10 men). None of these individuals had evidence of prior SARS-CoV-2 infection by history or by serology as described below. Informed consent was obtained from all study participants. All PLWH were on antiretroviral therapy and had a median CD4+ T cell count of 913 cells/ul (range of 649 to 1678 cells/ul). Eleven of the 12 PLWH were African American. 3 participants had low level viremia despite being on ART (supplementary Table). Peripheral blood mononuclear cells (PBMCs) and plasma were isolated from whole blood using ficoll centrifugation. We determined cellular immunity to the SARS-CoV-2 spike protein by performing an interferon-gamma (IFN-γ) Elispot assay with unfractionated PBMCs that were stimulated with a pool of overlapping SARS-CoV-2 spike peptides as previously described (7). The assay was also performed with CD8+ T cell depleted PBMCs to determine the relative contribution of CD4+ T cells and CD8+ T cells to the cellular immune response. The titer of SARS-CoV-2 spike binding antibodies was determined with the Euroimmun Anti-SARS-CoV-2 IgG ELISA (Mountain Lakes, NJ). Antibodies to the nucleocapsid protein were measured with the Bio-Rad Platelia SARS-CoV-2 Total Ab assay (Marnes-la-Coquette, France) and used to rule out natural infection with SARS-CoV-2 as mRNA for the nucleocapsid protein is not included in the vaccine. Measurement of antibodies in plasma that block SARS-CoV-2 Spike binding to ACE2 was performed with the MSD V-PLEX SARS-CoV-2 Panel 6 kit from Meso Scale Diagnostics (Rockville, MD) using a 1:100 dilution of plasma. Differences in Elispot and Euroimmun values were assessed using a two-tailed t-test. Differences in ACE2 blocking between groups was determined by a two-tailed Wilcoxon-Mann-Whitney test with a Bonferroni correction, employing R version 4.05. P-values < 0.05 were considered significant.
Abstract
Previous studies have shown that certain vaccines induce suboptimal responses in people living with HIV (PLWH). However, responses to SARS-CoV-2 vaccines have not been fully characterized in these patients. Here we show that the BNT162b2 vaccine induces robust immune responses comparable to responses in healthy donors.
Results
There was no significant difference in titers of SARS-CoV-2 spike binding antibodies in healthy donors (median value of 9.49) and PLWH (median value of 8.84 p=0.07) (Figure 1A). Furthermore, healthy donors and PLWH had similar levels of neutralizing antibodies to the vaccine strain spike protein (Figure 1B) and spike proteins from variants of concern (VOC) including the D614G, alpha (B.1.1.7), beta (B.1.351), and gamma (P.1) strains (Figures 1B-F). We next compared the cellular responses elicited by overlapping peptides from the vaccine strain spike protein in PLWH, to responses we obtained in healthy donors from a prior study (7). There was no significant difference in the number of IFN-γ spot forming units or in the stimulation index (values normalized to media alone) between healthy donors and PLWH in unfractionated PBMCs (Figure 1G, H) or with CD8+ T cell depleted PBMCs (Supplementary Figure 1). Finally, the breadth of the T cell response was comparable in the two groups and the similar peptide pools were targeted by the two study groups (Figure 1I).
Discussion
Our study is limited by the relatively small number of participants in both cohorts. While we screened participants for antibodies to nucleocapsid to rule out prior natural infection, the half-life of antibodies to this protein is relatively short (8). Thus we may have missed cases of prior SARS-CoV-2 infection. However, our data confirm a prior study showing that mRNA vaccines induce antibody responses in PLWH (5) and extend the findings by showing that the level of binding antibodies is not significantly different from that produced in healthy donors. These data are similar to results obtained in a phase 2/3 clinical trial in which the ChAdOx1 nCoV-19 (AZD1222) vaccine was shown to elicit strong SARS-CoV-2 specific antibody and T cell responses in PLWH (4). Of note, in a prior study of naturally infected individuals, antibody titers based on Euroimmun values above 8 were only seen in the top 10% of individuals, and were highly correlated with the highest levels of neutralizing titers based on a microneutralization assay (9). We also demonstrate that neither the magnitude and breadth of vaccine elicited T cell responses nor the breadth of neutralizing antibodies, as determined by responses to spike proteins from wild type virus and VOCs, is significantly different between PLWH and healthy donors.
These findings are particularly impressive as the PLWH study participants (median age 52 years, range 25 to 59) were older than the healthy donors (median age 41 years, range 24 to 59) and the BNT162b2 vaccine induces a lower antibody titer in older individuals (10). However, this vaccine also elicits a higher antibody titer in women compared to men (10) and our PLWH cohort had a higher frequency of female participants. Of note, prior vaccine studies in PLWH focused mainly (6) or exclusively on men (4). Data from our balanced cohort strongly suggest that the BNT162b2 vaccine will lead to protection from COVID-19 in men and women living with HIV. Further studies will be needed to determine whether PLWH with lower CD4 T cell counts have the same robust humoral and cellular responses to the vaccine.
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