ABSTRACT
Background: The biologic mechanisms underlying neurologic post-acute-sequelae of SARS-CoV-2 infection (PASC) are incompletely understood. We measured plasma markers of neuronal injury (glial fibrillary acidic protein [GFAP], neurofilament light chain [NfL]) and inflammation among a cohort of people with prior confirmed SARS-CoV-2 infection at early and late recovery following the initial illness (defined as < and > 90 days since COVID-19 onset, respectively). We hypothesized that those experiencing persistent neurologic symptoms would have elevations in these markers. Methods: The primary clinical outcome was the presence of self-reported central nervous system (CNS) PASC symptoms during the late recovery timepoint. We compared fold-changes in marker values between those with and without CNS PASC symptoms using linear mixed effects models and examined relationships between neurologic and immunologic markers using rank linear correlations. Results: Of 121 individuals, 52 reported CNS PASC symptoms. During early recovery, those who went on to report CNS PASC symptoms had elevations in GFAP (1.3-fold higher mean ratio, 95% CI 1.04-1.63, p=0.02), but not NfL (1.06-fold higher mean ratio, 95% CI 0.89-1.26, p=0.54). During late recovery, neither GFAP nor NfL levels were elevated among those with CNS PASC symptoms. Although absolute levels of NfL did not differ, those who reported CNS PASC symptoms demonstrated a stronger downward trend over time in comparison to those who did not report CNS PASC symptoms (p=0.041). Those who went on to report CNS PASC also exhibited elevations in IL-6 (48% higher during early recovery and 38% higher during late recovery), MCP-1 (19% higher during early recovery), and TNF-alpha (19% higher during early recovery and 13% higher during late recovery). GFAP and NfL correlated with levels of several immune markers during early recovery (MCP-1, IL-6, TNF-a, IFN-g);these correlations were attenuated during late recovery. Conclusion: Self-reported neurologic symptoms present approximately four months following SARS-CoV-2 infection are associated with elevations in markers of neurologic injury and inflammation at early recovery timepoints, suggesting that early injury can result in long-term disease. The correlation of GFAP and NfL with markers of systemic immune activation suggests one possible mechanism that might contribute to these symptoms. Additional work will be needed to better characterize these processes and to identify interventions to prevent or treat this condition.
ABSTRACT
Background: SARS-CoV-2 produces variable immune responses leading to different levels of immune protection. The relationship between neutralizing antibody level (NAb) and protective immunity has been well characterized after infection and vaccination. While comparatively specific T cell responses tend to be more variable, the impacts of these responses have broad implications on long-term immunity and their role in protective immunity has not been as clearly defined. Using data from our prospective cohort study and studies of clinical protective immunity/efficacy (from vaccines), we predicted protective immunity over time in relation to SARS-CoV-2-specific T cell dynamics. Methods: With linear mixed-effects models from our published immune data from people recovering from COVID-19, we simulated the Spike (S)-specific interferon-γ (IFNγ)+ CD4+, S-specific IFNγ+ CD8+, and nucleocapsid (N)-specific IFNγ+ CD8+ T cells over time (n=500 individuals). We then predicted NAbs from linear regression models developed from the same cohort. Finally, protective immunity from NAb titers was simulated from a published model. We similarly simulated 25, 50, and 75% lower T cell responses than those observed post-COVID-19 to understand how immune response variation may impact protective immunity. Results: Virus-specific T cell responses resulted in similar protective immunity across T cell subsets, but with differences in variability over time. Protective immunity for IFNγ+ S CD8 T cells spanned from 86-95%, while for IFNγ+ S CD4 T cells and IFNγ+ N CD4 T cells it ranged from 81-96% and 84-95% respectively. Further, based on simulated dampened T cell responses, protective immunity overall did not drop below 81% less than nine months after infection even with a 75% reduction in specific T cell immunity. Conclusion: NAbs are often the singular focus to predict protective immunity and the role of virus-specific T cell immunity has often been discussed as a secondary immune response. Our analysis demonstrates that for SARS-CoV-2, certain T cells responses can reliably predict protective immunity and may be intrinsically linked. Simulating dampened T cell response to mimic a more virulent strain or inadequate immune response, demonstrated that dampened T cell response may not be responsible for inadequate protective immunity in these scenarios. In the absence of prospective clinical data, similar models may be utilized to explore the impact of potential therapeutics on immune responses and resulting protective immunity.
ABSTRACT
Background. Limited data are available on whether there are differences in the immune response to SARS-CoV-2 vaccination by HIV status or by mRNA vaccine type. Methods. We saved residual outpatient laboratory samples of all previously mRNA-vaccinated individuals in the adult medicine clinics of a public hospital with a large outpatient HIV clinic during May 2021, and then excluded individuals with prior SARS-CoV-2 infection. We next 1:1 matched 100 PLWH to 100 outpatient HIVnegative adult medicine patients receiving care for chronic medical conditions on days since completion of second vaccination (minimum 10), sex, age +/-5 years, and the type of mRNA vaccine received. We defined a non-response as reciprocal pseudovirus neutralizing titer< 10 and anti-RBD IgG< 10 relative fluorescent units, and compared non-response by HIV status using mixed models. Results. In each matched group there were 13 women;25 received the mRNA-1273 vaccine and 75 received the BNT162b2 vaccine;the median age was 59. The median time from second vaccination was 35 days (IQR: 20-63). Among PLWH, the median CD4+ T-cell count was 511 (IQR: 351-796) and 5 individuals had HIV RNA > 200. We found 2.4-fold greater odds of pseudovirus neutralizing antibody non-response among PLWH compared to people without HIV (95% CI=1.1-5.4). Although few individuals in each group did not mount an IgG response (12 among PLWH vs. 5;p=0.08), continuous anti-RBD IgG concentrations were 43% lower among PLWH (95% CI=0.36-0.88). Among PLWH, when adjusting for age, sex, and days post-vaccination, each 100-cell increase in CD4+T-cell count was associated with 22% higher neutralizing antibody titers (GMR 1.22;95% CI=1.09-1.37). Unsuppressed HIV RNA >200 was associated with 89% lower neutralizing antibody titers (GMR 0.11;95% CI=0.01-0.84). Receipt of the BNT162b2 vs. mRNA-1273 vaccine was associated with 77% lower neutralizing titers (GMR 0.23;95% CI=0.08-0.65) among PLWH. Post-mRNA Vaccination SARS-CoV-2 IgG Concentrations and Pseudovirus Neutralizing Titers by HIV Status and Vaccine Conclusion. PLWH had lower than expected response to mRNA SARS-CoV-2 vaccines, with the highest non-response among those with low CD4+ counts, unsuppressed HIV RNA, and those who received the BNT162b2 vaccine. Immunization strategies to improve immune responses among PLWH should be studied, and may include booster vaccination or preference of the mRNA-1273 vaccine in this group.